Benzoxazine and benzothiazine derivatives and pharmaceutical compositions containing them

ABSTRACT

The present invention relates to novel antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds of formula (I) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them, to a process for preparing such compounds. More particularly, the present invention relates to novel alkyl carboxylic acids of the general, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them, to a process for preparing such compounds. The present invention also relates to processes for the preparation of the compounds of formula (I), novel intermediates, processes for their preparation, their use in the preparation of the above said compounds and their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds.

FIELD OF THE INVENTION

The present invention relates to novel antidiabetic, hypolipidemic,antiobesity and hypocholesterolemic compounds, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutically acceptable compositionscontaining them, to a process for preparing such compounds. Moreparticularly, the present invention relates to novel alkyl carboxylicacids of the general, their derivatives, their analogs, their tautomericforms, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts, their pharmaceutically acceptable solvates andpharmaceutically acceptable compositions containing them, to a processfor preparing such compounds.

The present invention also relates to novel intermediates, processes fortheir preparation, their use in the preparation of the above saidcompounds and their use as antidiabetic, hypolipidemic, antiobesity andhypocholesterolemic compounds.

The compounds of the present invention lower plasma glucose,triglycerides, lower total cholesterol (TC) and increase high-densitylipoprotein (HDL) and decrease low density lipoprotein (LDL), which havea beneficial effect on coronary heart disease and atherosclerosis.

The compounds of the present invention are useful in reducing bodyweight and for the treatment and/or prophylaxis of diseases such asatherosclerosis, stroke, peripheral vascular diseases and relateddisorders. These compounds are useful for the treatment ofhyperlipidemia, hyperglycemia, hypercholesterolemia, lowering ofatherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL.The compounds of the present invention can be used for the treatment ofcertain renal diseases including glomerulonephritis, glomerulosclerosis,nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. Thesaid compounds are also useful for the treatment and/or prophylaxis ofleptin resistance, impaired glucose tolerance, disorders related tosyndrome X such as hypertension, obesity, insulin resistance, coronaryheart disease and other cardiovascular disorders. These compounds mayalso be useful as aldose reductase inhibitors, for improving cognitivefunctions in dementia, treating diabetic complications, disordersrelated to endothelial cell activation, psoriasis, polycystic ovariansyndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonicdystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, eatingdisorders, inflammation and for the treatment of cancer. The compoundsof the present invention are also useful in the treatment and/orprophylaxis of the above said diseases in combination/concomittant withone or more HMG CoA reductase inhibitors,hypolipidemic/hypolipoproteinemic agents such as fibric acidderivatives, nicotinic acid, cholestyramine, colestipol and probucol;insulin, sulfonyl urea, metformin.

BACKGROUND OF THE INVENTION

Atherosclerosis and other peripheral vascular diseases effect thequality of life of millions of people. Therefore, considerable attentionhas been directed towards understanding the etiology ofhypercholesterolemia and hyperlipidemia and development of effectivetherapeutic strategies.

Hypercholesterolemia has been defined as plasma cholesterol level thatexceeds arbitrarily defined value called “normal” level. Recently, ithas been accepted that “ideal” plasma levels of cholesterol are muchbelow the “normal” level of cholesterol in the general population andthe risk of coronary artery disease (CAD) increases as cholesterol levelrises above the “optimum” (or “ideal”) value. There is clearly adefinite cause and effect-relationship between hypercholesterolemia andCAD, particularly for individuals with multiple risk factors. Most ofthe cholesterol is present in the esterified forms with variouslipoproteins such as Low density lipoprotein (LDL), Intermediate densitylipoprotein (IDL), High density lipoprotein (HDL) and partially as Verylow density lipoprotein (VLDL). Studies clearly indicate that there isan inverse correlationship between CAD and atherosclerosis with serumHDL-cholesterol concentrations, (Stampfer et al, N. Engl. J. Med., 325(1991), 373-381) and the risk of CAD increases with increasing levels ofLDL and VLDL.

In CAD, generally “fatty streaks” in carotid, coronary and cerebralarteries, are found which are primarily free and esterified cholesterol.Miller et al., (Br. Med. J., 282 (1981), 1741-1744) have shown thatincrease in HDL-particles may decrease the number of sites of stenosisin coronary arteries of human, and high level of HDL-cholesterol mayprotect against the progression of atherosclerosis. Picardo et al,Arteriosclerosis 6 (1986) 434-441 have shown by in vitro experiment thatHDL is capable of removing cholesterol from cells. They suggest that HDLmay deplete tissues of excess free cholesterol and transfer it to liver,which is known as reverse cholesterol transport, (Macikinnon et al., J.Biol. chem. 261 (1986), 2548-2552). Therefore, agents that increase HDLcholesterol would have therapeutic significance for the treatment ofhypercholesterolemia and coronary heart diseases (CHD).

Obesity is a disease highly prevalent in affluent societies and in thedeveloping world and is a major cause of morbidity and mortality. It isa state of excess body fat accumulation. The causes of obesity areunclear. It is believed to be of genetic origin or promoted by aninteraction between the genotype and environment. Irrespective of thecause, the result is fat deposition due to imbalance between the energyintake versus energy expenditure. Dieting, exercise and appetitesuppression have been a part of obesity treatment There is a need forefficient therapy to fight this disease since it may lead to coronaryheart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis,reduced fertility and many other psychological and social problems.

Diabetes and insulin resistance is yet another disease which severelyeffects the quality of large population in the world. Insulin resistanceis the diminished ability of insulin to exert its biological actionacross a broad range of concentrations. In insulin resistance, the bodysecretes abnormally high amounts of insulin to compensate for thisdefect; failing which, the plasma glucose concentration inevitablyraises and develops into diabetes. Among the developed countries,diabetes mellitus is a common problem and is associated with a varietyof abnormalities including obesity, hypertension, hyperlipidemia (J.Clin. Invest., 75 (1985) 809-817; N. Engl. J. Med 317 (1987) 350-357; J.Clin. Endocrinol. Metab., 66 (1988) 580-583; J. Clin. Invest., 68 (1975)957-969) and other renal complications (patent publication No. WO95/21608). It is now increasingly being recognized that insulinresistance and relative hyperinsulinemia have a contributory role inobesity, hypertension, atherosclerosis and type 2 diabetes mellitus. Theassociation of insulin resistance with obesity, hypertension and anginahas been described as a syndrome having insulin resistance as thecentral pathogenic link-Syndrome-X.

Hyperlipidemia is the primary cause for cardiovascular (CVD) and otherperipheral vascular disease's. High risk of CVD is related to the higherLDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein)seen in hyperlipidemia. Patients having glucose intolerance/insulinresistance in addition to hyperlipidemia have higher risk of CVD.Numerous studies in the past have shown that lowering of plasmatriglycerides and total cholesterol, in particular LDL and VLDL andincreasing HDL cholesterol help in preventing cardiovascular diseases.

Peroxisome proliferator acitivated receptors (PPAR) are members of thenuclear receptor super family. The gamma (γ) isoform of PPAR (PPARγ) hasbeen implicated in regulating differentiation of adipocytes(Endocrinology, 135, (1994) 798-800) and energy homeostasis (Cell, 83(1995) 803-812), whereas the alpha (α) isoform of PPAR (PPARα) mediatesfatty acid oxidation (Trend. Endocrin. Metab., 4 (1993) 291-296) therebyresulting in reduction of circulating free fatty acid in plasma (CurrentBiol. 5 (1995) 618-621). PPARα agonists have been found useful for thetreatment of obesity (WO 97/36579). It has been recently disclosed thatcompounds which are agonists for both PPARα and PPARγ are suggested tobe useful for the treatment of syndrome X (WO 97/25042). Similar effectbetween the insulin sensitizer (PPARγ agonist) and HMG CoA reductaseinhibitor has been observed which may be useful for the treatment ofatherosclerosis and xanthoma (EP 0 753 298).

It is known that PPARγ plays an important role in adipocytedifferentiation (Cell, 87 (1996) 377-389). Ligand activation of PPAR issufficient to cause complete terminal differentiation (Cell, 79 (1994)1147-1156) including cell cycle withdrawal. PPARγ is consistentlyexpressed in certain cells and activation of this nuclear receptor withPPARγ agonists would stimulate the terminal differentiation of adipocyteprecursors and cause morphological and molecular changes characteristicsof a more differentiated, less malignant state (Molecular Cell, (1998),465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., 94(1997) 237-241) and inhibition of expression of prostate cancer tissue(Cancer Research 58 (1998) 3344-3352). This would be useful in thetreatment of certain types of cancer, which express PPARγ and could leadto a quite nontoxic chemotherapy.

Leptin resistance is a condition wherein the target cells are unable torespond to leptin signal. This may give rise to obesity due to excessfood intake and reduced energy expenditure and cause impaired glucosetolerance, type 2 diabetes, cardiovascular diseases and such otherinterrelated complications. Kallen et al (Proc. Natl. Acad. Sci. (1996)93, 5793-5796) have reported that insulin sensitizers which perhaps dueto the PPAR agonist expression lower plasma leptin concentrations.However, it has been recently disclosed that compounds having insulinsensitizing property also possess leptin sensitization activity. Theylower the, circulating plasma leptin concentrations by improving thetarget cell response to leptin (WO 98/02159).

PRIOR ART

A few alkyl carboxylic acids, their derivatives and their analogs havebeen reported to be useful in the treatment of hyperglydemia andhypercholesterolemia. Some of such compounds described in the prior artare outlined below:i). In our international publication No. WO 99/08501 we have disclosedthe compounds of general formula (IIa)

wherein the groups R¹, R², R³, R⁴ and the groups R⁵ and R⁶ when attachedto carbon atom, nay be same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, acylamino,monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; one or both of R⁵ andR⁶ may also represent at oxo group when they are attached to carbonatom; R⁵ and R⁶ when attached to nitrogen atom represent hydrogen,hydroxy, formyl or unsubstituted or substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, amino, acylamino,monoalkylamino, dialkylamino, arylamino, aralkylamino, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylthio, carboxylic acidderivatives, or sulfonic acid derivatives; X represents a heteroatomselected from oxygen, sulfur, or NR¹¹ where R¹¹ represents hydrogen orunsubstituted or substituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, acyl, alkoxycarbonyl, ayloxycarbonyl or aralkoxycarbonylgroups; Ar represents unsubstituted or substituted divalent single orfused aromatic or heterocyclic group; R⁷ represents hydrogen atom,hydroxy, alkoxy, halogen, lower alkyl, unsubstituted or substitutedaralkyl group or forms a bond together with the adjacent group R⁸; R⁸represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl,unsubstituted or substituted aralkyl or R⁸ forms a bond together withR⁷; R⁹ represents hydrogen, unsubstituted or substituted groups selectedfrom alkyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl orheteroaralkyl groups; R¹⁰ represents hydrogen, unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl,acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y representsoxygen or NR¹², where R¹² represents hydrogen, alkyl, aryl,hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl groups;R¹⁰ and R¹² together may form a 5 or 6 membered cyclic structurecontaining carbon atoms, at least one nitrogen atom and which mayoptionally contain one or more additional heteroatoms selected fromoxygen, sulfur or nitrogen; the linking group represented by—(CH2)_(n)—(O)_(m)— may be attached either through a nitrogen atom or acarbon atom; n is an integer ranging from 14 and m is an integer 0 or 1.An example of these compounds is shown in formula (IIb)

ii) International publication No. WO 00/64888 disclose the compounds ofgeneral formula (IIc)

wherein Ar¹ and Ar² are independently aryl, fused arylcycloalkenyl,fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl,heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl,fused heteroarylcyclenyl or fused heteroarylheterocyclyl; A is O, S, SO,SO₂, NR¹³, C(O), NR¹⁴C(O), C(O)NR¹⁴, NR¹⁴C(O)N(R¹⁵), C(R¹⁴)═N; chemicalbond and the like; B is O, S, NR¹⁹, a chemical bond, C(O), N(R²⁰)C(O) orC(O)N(R²⁰); E is a chemical bond or an ethylene group; a is 0-6; b is0-4; c is 0-4; d is 0-6; g is 1-5; h is 1-4; R¹, R³, R⁵ and R⁷ areindependently hydrogen, halogen, alkyl, carbonyl, alkoxycarbonyl, oraralkyl; R², R⁴, R⁶ and R⁸ are independently —(CH₂)_(q)—X; q is 0-3; Xis hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy,heteroaralkoxy, carbonyl, alkoxycarbonyl, tetrazolyl, acyl, acylHNSO₂,and the like; Z is R²¹O₂C, R²¹OC, cyclo-imide; CN, R²¹O₂SHNCO, R²¹O₂SNH,R²¹NCO, R²¹O-2,4-thiazolidmonyl or tetrazolyl.

An example of these compounds is shown in formula (IId)

iii) International publication Nos. WO 95/03038 and WO 96/04260 disclosecompounds of formula (II e)

wherein R^(a) represents 2-benzoxazolyl or 2-pyridyl and R^(b) representCF₃, CH₂OCH₃ or CH₃. A typical example is(S)-3-[4-[2-[N-(2-benzoxazolyl)N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoicacid (II f).

iv) International publication Nos. WO 94/13650, WO 94/01420 and WO95/17394 disclose the compounds of general formula (II g)A¹-X-—(CH₂)_(n)—O-A²-A³-Y.R²   (II g)wherein A¹ represent aromatic heterocycle, A² represents substitutedbenzene ring and A³ represents moiety of formula (CH₂)_(m)—C—(OR¹),wherein R¹ represents alkyl groups, m is an integer of 1-5; X representssubstituted or unsubstituted N; Y represents C═O or C═S, R² representsOR³ where R³ may be hydrogen, alkyl, aralkyl, or aryl group and n is atinteger of 2-6.

An example of these compounds is shown in formula (II h)

v) International publication No. WO 00/49005 disclose the compounds ofgeneral formula (II i)

wherein Het is an optionally substituted, saturated partially saturatedor fully unsaturated 8 to 10 membered bicyclic ring, R¹ is optionallysubstituted aryl or optionally substituted heteroaryl, R² is hydrogenhalogen, lower alkyl or lower alkoxy, L¹ is an —R³—R⁴ linkage where R³is alkylene, alkenylene or alkynylene and R⁴ is a direct bond,cycloalkylene, heterocycloalkylene, arylene; heteroarylidinyl,—C(=Z²)-NR⁵, NR⁵—C(=Z²), -Z²-, —C(═O), —C(═NOR⁵)—, —NR⁵—, NR⁵—C(=Z²)NR⁵,SO₂—NR⁵ NR⁵—SO₂, —O—C(═O), —C(═O)—O, —O—C(═O)—NR⁵, —NR⁵—C(═O)—O—; L² isoptionally substituted alkylene or alkenylene, Y is carboxy or an acidbioisostere and Z¹ is NR⁵ and the corresponding N-oxides and theirprodrugs and pharmaceutically acceptable salts and solvates.

An example of these compounds is shown in formula (II j)

vi) International publication No. WO 94/12181 disclose the compounds ofgeneral formula (II k)X—Y-Z-Aryl-A-B   (II k)aryl is a 6 membered aromatic ring containing 0, 1, 2 or 3 nitrogenatoms and either unsubstituted or substituted with R⁸ and R⁹; Xrepresents NH₂, NH—C(═NH)—, and the like or 4 to 10 membered mono orpolycyclic aromatic or nonaromatic ring system and containing 0, 1, 2, 3or 4 heteroatoms selected from N, O or S either unsubstituted orsubstituted; Y is selected from C₀₋₈ alkyl, C₄₋₁₀ cycloalkyl, C₀₋₈alkyl-NR³—CO—C_(0.8) alkyl, C₀₋₈alkyl-CONR³—C₀₋₈ alkyl, C₀₋₈alkyl-O—C₀₋₈ alkyl, C₀₋₈ alkyl-S(O)_(n)—C₀₋₈ alkyl, (CH₂)₀₋₈aryl-(CH₂)₀₋₈, (CH₂)₀₋₆ aryl-SO_(n)—, (CH₂)₀₋₈ aryl-CO—(CH₂)₀₋₈,(CH₂)₀₋₆ aryl-SO₂—(CH₂)₀₋₆—, (CH₂)₀₋₆ NR³—(CH₂)₀₋₆—, (CH₂)₀₋₆aryl-CH(OH)—(CH₂)₀₋₆—, (CH₂)₀₋₈—CONH—(CH₂)₀₋₈—, C₀₋₈ alkyl-SO₂—NR³—C₀₋₈alkyl, C₀₋₈ alkyl-CO—C₀₋₈ alkyl, C₀₋₈ alkyl-CH(OH)—C₀₋₈ alkyl, where nis an integer from 0-2; Z and A are independently chosen from (CH₂)_(m),(CH₂)_(m)O(CH₂)_(n), (CH₂)_(m)NR³(C₂)_(n), (CH₂)_(m)NR³(CH₂)_(n),(CH₂)_(m)CONR¹¹(CH₂)_(n), (CH₂)_(m)CO(CH₂)_(n), (CH₂)_(m)CS(CH₂)_(n),(CH₂)_(m)SO₂(CH₂)_(n), (CH₂)_(m)S(CH₂)_(n), (CH₂)_(m)SO₂(CH₂)_(n),(CH₂)_(m)SO(CH₂)_(n), (CH₂)_(m)SO₂NR³(CH₂)_(n),(CH₂)_(m)NR³SO₂(CH₂)_(n), (CH₂)_(m)CR³═CR⁴(CH₂)_(n),(CH₂)_(m)C≡C(CH₂)_(n), (CH₂)_(m)CH(OH)(CH₂)_(n); where m and n are eachindependently an integer from 0 to 6; Aryl is a 6 membered aromatic ringsystem containing 0, 1, 2, 3 or 4 N atoms and either unsubstituted orsubstituted with R⁵, provided that when A is (CH₂)_(m), the Aryl ring,bonded by Z and A must contain at least one heteroatom;

-   -   B is        R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹, are independently selected from        hydrogen, fluorine, (C₁₋₈) alkyl, hydroxy, hydroxy(C₁₋₆) alkyl,        carboxy(C₀₋₆)alkyl, (C₁₋₆)alkyloxy, aryl(C₀₋₆)alkyloxy,        (C₃₋₈)cycloalkyl, aryl(C₀₋₆)alkyl, (C₁₋₆)alkylcarbonyloxy,        (C₀₋₆)alkylamino(C₀₋₆)alkyl and the like; R¹² is selected from        hydroxy, (C₁₋₈) alkyloxy, aryl (C₀₋₆) alkyl and the like;

An example of these compounds is shown in formula (II l)

vii) International publication No. WO 93/16697 and U.S. Pat. No.5,227,490 disclose the compounds of general formula (II m)

R¹ is chosen from hydrogen, C₁₋₆ alkyl, aryl C₄₋₁₀ alkyl, aryl, carboxy,C₁₋₆ alkyloxy, carboxy C₀₋₆ alkyl, carboxy C₁₋₆ alkyloxy, hydroxy C₀₋₆alkyl, C₁₋₄ alkylsulfonyl C₀₋₆ alkyl, C₀₋₄ alkylamino C₀₋₆ alkyl, arylC₀₋₁₀ alkylamino C₀₋₆ alkyl, C₂₋₁₀ acylamino C₀₋₆ alkyl, C₁₋₄carboalkoxy C₀₋₆ alkyl halogen, R² is independently chosen fromhydrogen, halogen, hydroxy, C₁₋₆ alkyl, wherein the alkyl group issubstituted or unsubstituted, C₁₋₆alkyloxy, aryl C₀₋₄ alkyl, aryl C₀₋₆alkyloxy and the like; R³ hydrogen, C₁₋₆ alkyl, aryl C₁₋₁₀ alkyl; Z isNR₄R⁵ or a 4-9 membered mono or bicyclic ring system containing 1, 2 or3 heteroatoms selected from N, O or S and either unsubstituted orsubstituted; Y is C₁₋₆ alkyl either unsubstituted or substituted, C₄₋₈cycloalkyl, aryl, —C(═O)NH—, —NH(C═O)— and the like; X is O, SO, SO₂, S,CO, —NR⁴CO—, CONR⁴—, CH₂ and the like;

An example of these compounds is shown in formula (II n)

Few β-phenyl α-hydroxysubstituted propionic acid derivatives have beenreported which have been used as intermediates for the synthesis oftarget molecules. Some of such compounds described in the prior art areoutlined below:i) European Patent Application EP0816316 discloses compound of formula(IIo)

The compound of formula (va) was further converted to 1,2-ethainediaolderivative of the formula (IIp):

These 1,2-ethanediaol derivatives are useful intermediates for thepharmaceuticals and agricultural chemicals.ii) Japanese Patent Application JP 10017540 discloses compound offormula (IIq)

The compound of formula (IIr) was further converted to a compound offormula (vd)

SUMMARY OF THE INVENTION

With an objective to develop novel compounds for the treatment and/orprophylaxis of diseases related to increased levels of lipids,especially to treat hypertriglyceridemia and to lower free fatty acids,for the treatment and/or prophylaxis of diseases described as Syndrome-Xwhich include hyperlipidemia, hyperinsulinemia, obesity, insulinresistance, insulin resistance leading to type 2 diabetes and diabetescomplications thereof, for the treatment of diseases wherein insulinresistance is the pathophysiological mechanism, for the treatment ofhypertension, atherosclerosis and coronary artery diseases with betterefficacy, potency and lower toxicity, we focused our research to developnew compounds effective in the treatment of above mentioned diseases.

The main objective of the present invention is therefore, to providenovel β-aryl-α-oxysubstituted alkylcarboxylic acids and theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them, or their mixtures.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkyl carboxylic acids, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutical compositions containing them ortheir mixtures which may have agonist activity against PPARα and/orPPARγ, and optionally inhibit HMG CoA reductase, in addition to agonistactivity against PPARα and/or PPARγ.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkyl carboxylic acids and their derivatives,their analogs, their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them or their mixtures having enhanced activities, withouttoxic effect or with reduced toxic effect.

Yet another objective of the present invention is to provide a processfor the preparation of β-aryl-α-oxysubstituted alkyl carboxylic acids,their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptable saltsand their pharmaceutically acceptable solvates.

Still another objective of the present invention is to providepharmaceutical compositions of β-aryl-α-oxysubstituted alkyl carboxylicacids, their analogs, their derivatives, their tautomers, theirpolymorphs, their salts, solvates or their mixtures in combination withsuitable carriers, solvents, diluents and other media normally employedin preparing such compositions.

Another objective of the present invention is to provide novelintermediates, a process for their preparation and use of theintermediates in process for preparation of β-aryl-α-oxysubstitutedalkoxy carboxylic acids, their derivatives, their analogs theirtautomers, their stereoisomers, their polymorphs, their salts and theirpharmaceutically acceptable solvates and their use as antidiabetic,hypolipdemic, antiobesity and hypocholesterolemic compounds.

DETAILED DESCRIPTION OF THE INVENTION

β-Aryl-α-oxysubstituted propionoic acids of the present invention havingthe general formula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates wherein R¹, R² and R³,R⁴ when attached to the carbon atom, may be same or different andrepresent hydrogen, halogen, hydroxy, nitro, cyano, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R³ and R⁴ may represent oxo or thioxo group when they areattached to carbon atom; R³ and R⁴ when attached to nitrogen atomrepresent hydrogen, hydroxy, formyl or substituted or unsubstitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy,heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid derivatives, or sulfonic acid derivatives; X representsa heteroatom selected from oxygen or sulfur; W represents NR¹²,—C(═O)CR¹⁰R¹¹)_(o)—NR¹², -O-aryl-(CR¹⁰R11)_(o)—NR¹², where R¹²represents hydrogen or substituted or unsubstituted group selected fromalkyl, aryl or aralkyl groups; o is an integer ranging from 0-6; R¹⁰ andR¹¹ may be same or different and represent hydrogen or unsubstituted orsubstituted group selected form alkyl, alkoxyl, aryl or aralkyl group;Ar represents substituted or unsubstituted diavlent single or fusedaromatic or heterocyclic group; R⁵ represents hydrogen atom, hydroxy,alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group orforms a bond together with the adjacent group R⁶; R⁶ representshydrogen, hydroxy, alkoxy, halogen, alkyl group, acyl, substituted orsubstituted aralkyl or R⁶ forms a bond together with R⁵; R⁷ may behydrogen or substituted or unsubstituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, aryl, arylaminocarbonyl, acyl, heterocyclyl,heteroaryl, heteroaralkyl groups, R⁸ may be hydrogen or substituted orunsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen,sulfur or NR⁹, where R⁹ represents hydrogen or substituted orunsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkylheterocyclyl, heteroaryl, or heteroaralkyl groups or NR⁹ representschiral amine, chiral amine alcohols derived from chiral amino acid; R⁸and R⁹ together may form a substituted or unsubstituted 5 or 6 memberedcyclic structure containing carbon atoms, which may optionally containone or more heteroatoms selected from oxygen, sulfur or nitrogen m and nare integers ranging from 0-6.

Suitable groups represented by R¹, R², R³, R⁴, may be selected fromhydrogen, halogen atom such as fluorine, chlorine, bromine or iodine;hydroxy, cyano, nitro, formyl, substituted or unsubstituted (C₁-C₂)alkyl group especially linear or branched (C₁-C₁₀) alkyl group such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl,n-pentyl, iso-pentyl, hexyl, heptyl, octyl and, the like;cyclo(C₃-C6)alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like, the cycloalkyl group may be substituted;(C₁-C₆)alkoxy such as methoxy, ethoxy, propyloxy, butyloxy,iso-propyloxy and the like, which may be substituted; cyclo(C₃-C6)alkoxygroup such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy and the like, the cycloalkoxy group may be substituted;aryl group such as phenyl, naphthyl and the like, the aryl group may besubstituted; aryloxy group such as phenoxy, naphthyloxy and the like,the aryloxy group may be substituted; aralkyl such as benzyl, phenethyl,C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, the aralkyl group may besubstituted; aralkoxy group such as benzyloxy, phenethyloxy,naphthylmethyloxy, phenylpropyloxy and the like, the aralkoxy group maybe substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl,morpholinyl, piperidinyl, piperazinyl and the like, the heterocyclylgroup may be substituted; heteroaryl group such as pyridyl, thienyl,furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl,tetrazolyl, benzopyranyl, benzofuryl and the like, the heteroaryl groupmay be substituted; heteroaralkyl group such as furanmethyl,pyridinemethyl, oxazolemethyl, oxazolethyl and the like, theheteroaralkyl group may be substituted; heteroaryloxy andheteroaralkoxy, wherein heteroaryl and heteroaralkyl moieties are asdefined earlier and may be substituted; acyl group such as acetyl,propionyl, benzoyl and the like, the acyl group may be substituted;acyloxy group such as OOCMe, OOCEt, OOCPh and the like, which may besubstituted, acylamino groups such as NHCOCH₃, NHCOC₂H₅, NHCOC₃H₇,NHCOC₆H₅ and the like, which may be substituted; monoalkylamino groupsuch as —NHCH₃, NHC₂H₅, NHC₃H₇, NHC₆H₁₃, and the like, which may besubstituted; dialkylamino group such as N(CH₃)₂, NCH₃(C₂H₅), N(C₂H₅)₂and the like, which may be substituted; arylamino group such as HNC₆H₅,NCH₃(C₆H₅), NHC₆H₄CH₃, NHC₆H₄-Hal and the like, which may besubstituted; aralkylamino group such as C₆H₅CH₂NH, C₆H₅CH₂CH₂NH,C₆H₅CH₂NCH₃ and the like, which may be substituted; amino group;alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like,which may be substituted; aryloxycarbonyl group such as phenoxycarbonyl,naphthyloxycarbonyl and the like, the aryloxycarbonyl group may besubstituted; aralkoxycarbonyl group such as benzyloxycarbonyl,phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may besubstituted; alkoxyalkyl group such as methoxymethyl, ethoxymethyl,methoxyethyl, ethoxyethyl and the like, the alkoxyalkyl group may besubstituted; aryloxyalkyl group such as C₆H₅OCH₂, C₆H₅OCH₂CH₂,naphthyloxymethyl and the like, which may be substituted; aralkoxyalkylgroup such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂ and the like, which may besubstituted; hydroxy(C₁-C₆)alkyl, which may be substituted; thio(C₁-C₆)alkyl, which may be substituted; (C₁-C₆)alkylthio which may besubstituted; alkoxycarbonylamino group such as NHCOOC₂H₅, NHCOOCH₃ andthe like, which may be substituted; aryloxycarbonylamino group such asNHCOOC₆H₅, NCH₃COOC₆H₅, NC₂H₅COOC₆H₅, NHCOOC₆H₄CH₃, NHCOOC₆H4OCH₃ andthe like, which may be substituted; aralkoxycarbonylamino group such asNHCOOCH₂C₆H₅, NHCOOC₂CH₂C₆H₅, N(CH₃)COOCH₂C₆H₅, N(C₂H₅)COOCH₂C₆H₅,NHCOOCH₂C₆H₄CH₃, NHCOOCH₂C₆H₄OCH₃ and the like, which may besubstituted; carboxylic acid or its derivatives such as amides, likeCONH₂, CONHMe, CONMe₂, CONHEt, CONEt, CONEt₂, and the like, thecarboxylic acid derivatives may be substituted; sulfonic acid or itsderivatives such as SO₂NH₂, SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ and the like, thesulfonic acid derivatives may be substituted.

When the groups represented by R¹ to R⁴ are substituted, thesubstituents may be selected from halogen, hydroxy, nitro, nitro orunsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl,acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino aminoalkyl,alkoxycarbonyl, alkylamino, alkylthio groups, carboxylic acids or itsderivatives or sulfonic acid or its derivatives. These groups are asdefined above.

It is preferred that the substituents on R¹ to R⁴ represent halogen atomsuch as fluorine, chlorine or bromine; alkyl group such as methyl,ethyl, iso-propyl, n-propyl, n-butyl; cycloalkyl group such ascyclopropyl; aryl group such as phenyl; aralkyl group such as benzyl;(C₁-C₃)alkoxy, benzyloxy, hydroxy, acyl or acyloxy groups.

Suitable groups represented by X may be selected from oxygen or sulfur.

Suitable groups represented by Ar may be selected from substituted orunsubstituted groups selected from divalent phenylene, naphthylene,pyrrol, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl,benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl,azaindolyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. Thesubstituents on the group represented by Ar amy may be selected fromlinear or branched optionally halogenated (C₁-C₆)alkyl, optionallyhalogenated (C₁-C₃)alkoxy, halogen, acyl, amino, acylamino, thio orcarboxylic or sulfonic acids and their derivatives. The substituents aredefined as they are for R¹—R⁴.

It is more preferred that Ar represent substituted or unsubstituteddivalent, phenylene, naphthylene, benzofuryl, indolyl, indolinyl,quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolylgroups.

Suitable groups represented by R⁵ may be selected from hydrogen,hydroxy, (C₁-C₆) alkyl groups such as methyl, ethyl, propyl and thelike; (C₁-C₃)alkoxy group such as methoxy, ethoxy, propoxy and the like;halogen atom such as fluorine, chlorine, bromine or iodine; aralkyl suchas benzyl, phenethyl and the like, which may be unsubstituted orsubstituted or R⁵ together with R⁶ represents a bond. The substituentsare selected from halogen, hydroxy or alkyl groups.

Suitable R⁶ may be hydrogen, hydroxy, (C₁-C6)alkyl groups such asmethyl, ethyl, propyl and the like; (C₁-C₃)alkoxy such as methoxy,ethoxy, propoxy and the like; halogen atom such as fluorine, chlorine,bromine or iodine; (C₂-C₁₀)acyl group such as acetyl, propanoylbutanoyl, pentanoyl, benzoyl and the like; aralkyl such as benzyl,phenethyl and the like, which may be unsubstituted or substituted or R⁶together with R⁵ forms a bond. The substituents are selected fromhalogen, hydroxy or alkyl groups.

Suitable groups represented by R⁷ may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group such as methylethyl, n-propyl, iso-propyl, n-butyl iso-butyl, pentyl, hexyl, octyl andthe like, the alkyl group may be substituted; (C₃-C7)cycloalkyl groupsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like,the cycloalkyl group may be substituted; aryl group such as phenyl,naphthyl and the like, the aryl group may be substituted; aralkyl groupsuch as benzyl, phenethyl and the like, wherein the alkyl moiety maycontain (C₁-C₆) atoms, wherein the aryl moiety may be substituted;heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the like,the heteroaryl group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; heterocyclyl group such asaziridinyl, pyrrolidinyl piperidinyl and the like, the heterocyclylgroup may be substituted; linear or branched (C₂-C₆)acyl group such asacetyl, propanoyl, butanoyl, benzoyl, octanoyl, decanoyl and the like,which may be substituted; (C₁-C₆)alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl and the like, the alkoxycarbonyl groupmay be substituted; aryloxycarbonyl such as phenoxycarbonyl,naphthyloxycarbonyl and the like, the aryl group may be substituted;(C₁-C₆)alkylaminocarbonyl, the alkyl group may be substituted;arylaminocarbonyl such as PhNHCO, naphthylaminocarbonyl and the like,the aryl moiety may be substituted. The substituents may be selectedfrom halogen, hydroxy, nitro or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy,aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl,alkylthio, thioalkyl groups, carboxylic acid or its derivatives orsulfonic acid or its derivatives. The substituents are as defined above.

Suitable groups represented by R⁸ may be selected from hydrogen, linearor branched (C₁C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyland the like, the alkyl group may be substituted; (C₃-C₇)cycloalkyl suchas cyclopropyl, cyclopentyl, cyclohexyl and the like, the cycloalkylgroup may be substituted; aryl group such as phenyl, naphthyl and thelike, the aryl group may be substituted; heteroaryl group such aspyridyl, thienyl, pyrrolyl, furyl and the like, the heteroaryl group maybe substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl,oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may besubstituted; aralkyl group such as benzyl, phenethyl and the like, thearalkyl group may be substituted; heterocyclyl group such a aziridinyl,pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may besubstituted. The substituents on R⁸ may be selected from halogen,hydroxy, nitro or unsubstituted or substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy,alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid or its derivatives, or sulfonic acid or its derivatives.The substituents are as defined above.

Suitable groups represented by R⁹ may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group, such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl,heptyl, octyl and the like, hydroxy(C₁-C₆)alkyl; aryl group such asphenyl, naphthyl and the like; aralkyl group such as benzyl, phenethylthe like; heterocyclyl group such as aziridinyl, pyrrolidinyl,piperidinyl and the like; heteroaryl group such as pyridyl, thienyl,pyrrolyl, furyl and the like; heteroaralkyl group such as furanmethyl,pyridinemethyl, oxazolemethyl, oxazolethyl and the like. Thesubstituents may be selected from hydroxy, halogen, nitro, amino, alkyl,alkoxy or aryl.

Suitable chiral amines represented by NR⁹ may be selected fromR(+)-α-ethylphenylamine, naphthylethylamine, S(+) phenylglycinol,cinchonidine, ephedrine, N-octylglucaramine, N-methylglucaramine and thelike; chiral amine alcohols such as phenyl glycinol, valine,tert-leucine and the like.

Suitable ring structures formed by R⁸ and R⁹ together may be selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.

Suitable groups represented by R¹⁰ and R¹¹ may be selected fromhydrogen, or substituted or unsubstituted linear or branched(C₁-C₁₂)alkyl group, such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl,nonyl, decyl and the like; (C₁-C₆)alkoxy such as methoxy, ethoxy,propyloxy, butyloxy, iso-propyloxy and the like, which may besubstituted; aryl group such as phenyl, naphthyl and the like, the arylgroup may be substituted; aralkyl such as benzyl, phenethyl,C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like. The substituents may beselected from hydroxy, halogen, nitro or amino.

Suitable groups represented by R¹² may be selected from hydrogen orsubstituted or unsubstituted linear or branched (C₁-C₁₂)alkyl group suchas methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl,n-pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like;aryl group such as phenyl, naphthyl and the like, the aryl group may besubstituted; aralkyl group such as benzyl, phenethyl C₆H₅CH₂CH₂CH₂,naphthylmethyl and the like the substituents may be selected fromhydroxy, halogen, nitro or amino.

Suitable n is an integer ranging from 0 to 6.

Suitable m is an integer ranging from 0 to 6.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, Mn; salts of organic bases such as N,N′-diacetylethylenediamine,betaine, caffeine, 2-diethylaminoethanol, 2 -dimethylaminoethanol,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,hydrabamine; isopropylamine, methylglucamine, morpholine, piperazine,piperidine, procaine, purines, theobromine, glycinol, diethylamine,triethylamine, trimethylamine, tripropylamine, tromethamine, adamentylamine, diethanolamine, meglumine, ethylenediamine,N,N′-diphenylethylethlendiamine, N,N′-dibenzylthylenediamine, N-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine,metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine,thiamine, aminopyrimdine, aminopyridine, purine, spermidine, and thelike; chiral bases like alklphenylamine, phenyl glycinol and the like,salts of natural amino acids such as glycine, alanine, valine, leuucine,isoleucine, norleucine, tyrosine, cytosine, cysteine, methionine,proline, hydroxy proline, histidine, ornithine, lysine, arginine,serine, threonine, phenylalanine; unnatural amino acids such asD-isomers or substituted amino acids; guanidine, substituted guanidinewherein the substituents are selected from nitro, amino, alkyl, alkenyl,alkynyl, ammonium or substituted ammonium salts and aluminum salts.Salts may include acid addition salts where appropriate which are,sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides,acetates, tartrates, maleates, citrates, succinates, palmoates,methanesulphonates, benzoates, salicylates, hydroxynaphthoates,benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and thelike. Pharmaceutically acceptable solvates may be hydrates or comprisingother solvents of crystallization such as alcohols.

Particularly useful compounds according to the present inventionincludes:

-   -   (±) Ethyl        3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;    -   (+) Ethyl        3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;    -   (−) Ethyl        3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;    -   (±)        3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (+)        3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (−)        3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (±) Ethyl        3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate;    -   (+) Ethyl        3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate;    -   (−) Ethyl        3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate;    -   (±)        3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (+)        3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (−)        3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (±) Methyl        2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propionate;    -   (+) Methyl        2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate;    -   (−) Methyl        2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate;    -   (±)        2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoic        acid or its salts;    -   (+)        2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoic        acid or its salts;    -   (−)        2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoic        acid or its salts;    -   (±) Methyl        3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate;    -   (+) Methyl        3-[4-{5-(3,4)-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate    -   (−) Methyl        3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate;    -   (±)        3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (+)        3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (−)        3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (±) Methyl        3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;    -   (+) Methyl        3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl)-2-ethoxypropanoate;    -   (−) Methyl        3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;    -   (±)        3-[3-{3(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (+)        3-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (−)        3-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (±) Methyl        3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate;    -   (+) Methyl        3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate;    -   (−) Methyl        3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b]b[1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate;    -   (±)        3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (+)        3-[4-{3-(7-Fluoro-3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (−)        3-[4-{3-(7-Fluoro-3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts;    -   (±) Methyl        2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;    -   (+) Methyl        2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;    -   (−) Methyl        2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;    -   (±) Methyl        2-ethoxy-3-[3-{4-(3-(3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;    -   (+) Methyl        2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;    -   (−) Methyl        2-ethoxy-3-[3-{4-(3-(3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;    -   (±)        2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)        benzyl}aminophenyl]propanoic acid or its salts;    -   (+)        2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)        benzyl}aminophenyl]propanoic acid or its salts;    -   (−)        2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)        benzyl}aminophenyl]propanoic acid or its salts;    -   (±)        2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)        benzyl}aminophenyl]propanoic acid or its salts;    -   (+)        2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)        benzyl}aminophenyl]propanoic acid or its salts;    -   (−)        2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)        benzyl}aminophenyl]propanoic acid or it salts;    -   (±) Ethyl        2-ethoxy-3-[4-{3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate;    -   (+) Ethyl        2-ethoxy-3-[4-{3-(3,4-dihydro-2-benzo[b[1,4]thiazin-4-yl)propylamino}phenyl]propanoate;    -   (−) Ethyl        2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate;    -   (±)        2-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoic        acid or its salts;    -   (+)        2-Ethoxy-3-[4-{3-(3,4dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl)propanoic        acid or its salts;    -   (−)        2-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoic        acid or its salts;    -   (±) Ethyl        2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        ethylamino}phenyl]propanoate;    -   (+) Ethyl        2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        ethylamino}phenyl]propanoate;    -   (−) Ethyl        2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        ethylamino}phenyl]propanoate;    -   (±)        2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoic        acid or its salts;    -   (+)        2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoic        acid or its salts;    -   (−)        2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoic        acid or its salts;    -   (±) Methyl        2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate;    -   (+) Methyl        2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate;    -   (−) Methyl        2-ethoxy-3-[4-[4-{2-(3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate;    -   (±)        2-Ethoxy-3-[4-[4-{2-(3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoic        acid or its salts;    -   (+)        2-Ethoxy-3-[4-[4-{2-(3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoic        acid or its salts;    -   (−)        2-Ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoic        acid or its salts;    -   (±) Ethyl        3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (+) Ethyl        3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl -2-ethoxypropanoate    -   (−) Ethyl        3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (±) Ethyl        3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (+) Ethyl        3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b[1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (−) Ethyl        3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (±)        3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid or its salts    -   (+)        3-[4-{3-(Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid or its salts    -   (−)        3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid or its salts    -   (±) Ethyl        3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (+) Ethyl        3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (−) Ethyl        3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-[b][b][1,4]oxazin-4-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (±)        3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts    -   (+)        3-[4-(3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts    -   (−)        3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts    -   (±) Ethyl        3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (+) Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H        -benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (−) Ethyl        3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (±)        3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts    -   (+)        3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts    -   (−)        3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl)-2-ethoxypropanoic        acid or its salts    -   (±) Ethyl        3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (+) Ethyl        3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (−) Ethyl        3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (±)        3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid or its salts    -   (+)        3-[4-{3-(2-methyl-3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid or its salts    -   (−)        3-[4-{3-(2-methyl-3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid or its salts    -   (±) Ethyl        3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (+) Ethyl        3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (−) Ethyl        3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-ethoxypropanoate    -   (±)        3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts    -   (+)        3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts    -   (−)        (3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic        acid or its salts    -   (±) Ethyl        (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (+) Ethyl        (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (−) Ethyl        (2S)-3-[4-{3(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (±)        3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid and its salts    -   (+) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4        ]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid and its        salts    -   (−)        3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid and its salts    -   (±) Ethyl        2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]propanoate    -   (+) Ethyl        2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]propanoate    -   (−) Ethyl        2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]propanoate    -   (±) 2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b        ][1,4]oxazin-4-yl) propylamino}phenyl]propanoic acid and its        salts    -   (+)        2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]propanoic acid and its salts    -   (−)        2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]propanoic acid and its salts    -   (±) Ethyl        3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (+) Ethyl        3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (−) Ethyl        3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)        propylamino}phenyl]-2-methoxypropanoate    -   (±)        3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid and its salts    -   (+)        3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid and its salts    -   (−)        3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic        acid and its salts    -   [2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;    -   [2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;    -   2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide    -   [2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide    -   [2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide        hydrochloride salt;    -   [2R,N(1R)]-N-(2-hydroxy-1-phenylethoxy)-2-ethoxy-3-[4-{3-(3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide        hydrochloride salt;

According to another embodiment of the present invention, the compoundof general formula (I) where R⁵ and R⁶ together represent a bond; Yrepresent oxygen or sulfur and W represents N¹²,—O-aryl-(CR¹⁰R¹¹)_(o)—NR¹²—, and all other symbols are as defined abovemay be prepared by one or more of processes shown in Scheme-I below.

Route (1): The reaction of a compound of the general formula (IIIa)where L¹ is a leaving group such as halogen atom, metanesulfonate,trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenznensulfonate,acetate, sulfate, phosphate, hydroxy and the like, and all other symbolsare as defined above with compound of formula (IIIb) where W representsNR¹², —O-aryl-(CR¹⁰R¹¹)_(o)—NR¹²—; and all other symbols are as definedabove to yield compound of general formula (I) where all symbols are asdefined above may be carried out in the presence of a base such as metalcarbonates like sodium carbonate, potassium carbonate, calciumcarbonate, cesium carbonate and the like; metal bicarbonates like sodiumbicarbonate, potassium bicarbonate, cesium bicarbonate and the like;metal hydrides like NaH or KH; metal hydroxides, like sodium hydroxide,potassium hydroxide, calcium hydroxide, cesium hydroxide and the like;alkoxides such as NaOMe, NaOEt, K⁺BuO⁻ and the like; organic bases suchas guanidine, triethyl amine, pyridine, N-methyl morpholine and the likeor mixtures thereof. The reaction may be carried out in the presence ofsolvents such as THF, dioxane, DMF, DMSO, DME, toluene, benzene,acetone, dimethyl acetamide, acetonitrile and the like or mixturesthereof Phase transfer catalyst such as tetraalkylammonium halides orhydroxides may be employed. The reaction temperature may range from 0°C. to 150° C., preferably at a temperature in the range of 10° C. to120° C. When L1 represents, hydroxy group, the reaction may also becarried out using Mitsunobu conditions using reagents lie DEAD, DIAD andthe like. The compound of formula (IIIa) was obtained by reactingcompound of the formula (IVc)

where all symbols are as defined earlier, with a compound of formula(IVd)L¹-(CR¹⁰R¹¹)_(n)-L¹   (IV d)where L¹ and all other symbols are as defined above.

Route (2): The reaction of a compound of general formula (IIIc) whereall symbols are as defined above with a compound of general formula(IIId) where L¹ is a leaving group such as halogen atom,methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate,p-nitrobenznensulfonate, acetate, sulfate, phosphate, hydroxy and thelike, and all other symbols are as defined above to yield compound ofgeneral formula (I) where all symbols are as defined above may becarried out in the presence of a base such as metal carbonates likesodium carbonate, potassium carbonate, calcium carbonate, cesiumcarbonate and the like; metal bicarbonates like sodium bicarbonate,potassium bicarbonate, cesium bicarbonate and the like; metal hydrideslike NaH or KH; metal hydroxides, like sodium hydroxide, potassiumhydroxide, calcium hydroxide, cesium hydroxide and the like; alkoxiodessuch as NaOMe, NaOEt, K⁺BuO⁻ and the like; organic bases such asguanidine, triethyl amine, pyridine, N-methyl morpholine and the like ormixtures thereof. The reaction may be carried out in the presence ofsolvents such as THF, dioxane, DMF, DMSO, DME, toluene, benzene,acetone, dimethyl acetamide, acetonitrile and the like or mixturesthereof. Phase transfer catalyst such as tetraalkylammonium halides orhydroxides may be employed. The reaction temperature may range from 0°C. to 150° C., preferably at a temperature in the range of 10° C. to100° C. When L¹ represents, hydroxy group, the reaction may be also becarried out using Mitsunobu conditions using reagents lie DEAD, DIAD andthe like.

Route (3): The reaction of a compound of the general formula (IIIe)where all symbols are as defined above with a compound of formula (IIIf)where R¹³ represents (C₁-C₆)alkyl group and all other symbols are asdefined earlier to yield compound of general formula (I) where R⁵ and R⁶together represent a bond and all other symbols are as defined above maybe carried out in the presence of a base such as metal hydride such asNaH or KH; organolithiums such as CH₃Li, BuLi and the like; alkoxidessuch as NaOMe, NaOEt, K⁺BuO⁻ and the like or mixtures thereof. Thereaction may be carried out in the presence of solvents such as diethylether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like ormixtures thereof. HMPA may be used as cosolvent. The reactiontemperature may range from −78° C. to 50° C., preferably at atemperature it the range of −10° C. to 30° C. The reaction is moreeffective under anhydrous conditions. The compound of general formula(IIIf) may be prepared according to the procedure described in theliterature (Annalen. Chemie, (1996)53, 699).

According to another embodiment, of the present invention, the compoundof the general formula (I) where R⁵ represents hydrogen atom, hydroxy,alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl grouprepresents hydrogen, hydroxy, alkoxy, halogen, alkyl group, acyl,substituted or unsubstituted aralkyl; Y represents oxygen and Wrepresents NR¹², —O-aryl-(CR¹⁰R¹¹)_(o)—NR¹²—; and all other symbols areas defined above may be prepared by one or more of processes shown inScheme-II below.

Route (4): The reduction of compound of the formula (IVa) whichrepresents a compound of formula (I) where R⁵ and R⁶ represent a bondand Y represents oxygen atom and all other symbols are as definedearlier, obtained as described earlier in Scheme-I, to yield a compoundof the general formula (I) where R⁵ and R⁶ each represent hydrogen atomand all symbols are as defined earlier, may be carried out in thepresence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C,Raney nickel and the like. Mixtures of catalysts may be used. Thereaction may also be conducted in the presence of solvents such asdioxane, acetic acid, ethyl acetate, methanol, ethanol, isopropanol andthe like. A pressure between atmospheric pressure and 80 psi may beemployed. High pressures may be used to reduce the reaction time. Thecatalyst may be preferably 5-10 % Pd/C and the amount of catalyst usedmay range from 1-50% w/w. The reaction may also be carried out byemploying metal solvent reduction such as magnesium, samarium in alcoholor sodium amalgam in alcohol, preferably methanol. The hydrogenation maybe carried out in the presence of metal catalysts containing chiralligands to obtain a compound of formula (I) in optically active form.The metal catalyst may contain Rhodium, Ruthenium, Indium and the like.The chiral ligands may preferably be chiral phosphines such as(2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane,1,2-bis(2-methoxyphenylphenylphosphino)ethane,(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butaneand the like. Any suitable chiral catalyst may be employed which worldgive required optical purity of the product (I).

Route (5): The reaction of a compound of the general formula (IIIe)where L¹ is a leaving group such as halogen atom, methanesulfonate,trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenznensulfonate,acetate, sulfate, phosphate, hydroxy and the like, and all other symbolare as defined above with a compound of formula (IVb) where R⁵represents hydrogen and all other symbols ate as defined earlier toyield compound of general formula (I) where R⁵ and R⁶ represent ahydrogen atom and all other symbols are as defined above may be carriedout in the presence of a base such as metal hydride such as NaH or KH;organolithiums such as CH₃Li, LiN(iPr)₂, LiHMDS, LiN(Et)₂, NaHMDS,KHMDS, BuLi and the like; alkoxides such as NaOMe, NaOEt, t-BuO⁻K⁺ andthe like mixtures thereof. The reaction nay be carried out in thepresence of solvents such as diethyl ether, THF, dioxane, DMF, DMSO,DME, dimethyl acetamide and the like or mixtures thereof. HMPA may beused as cosolvent. The reaction temperature may range from −78° C. to50° C., preferably at a temperature in the range of −10° C. to 30° C.The reaction is more effective under anhydrous conditions

According to another embodiment of the present invention, the compoundof the general formula (I) where Y represents oxygen or sulfur and Wrepresents —C(═O)—(CR¹⁰OR¹¹)_(o)—NR¹²— where o is an integer rangingfrom 0-6 and all other symbols are as defined above may be prepared by aprocess which comprises reacting the compound of formula (IIIg)

where L¹ is a leaving group such as halogen atom, methanesulfonate,trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenznensulfonate,acetate, sulfate, phosphate, hydroxy and the like, and all other symbolsare as defined above with compound of formula (IIIb)

where W represents NR¹², R¹² represents hydrogen and all other symbolsare as defined above in the presence of a base such as metal carbonateslike sodium carbonate, potassium carbonate, calcium carbonate, cesiumcarbonate and the like; metal bicarbonates like sodium bicarbonate,potassium bicarbonate, cesium bicarbonate and the like; metal hydrideslike NaH or KH; metal hydroxides, like sodium hydroxide, potassiumhydroxide, calcium hydroxide and the like; alkoxides such as NaOMe,NaOEt, K⁺BuO⁻ and the like; organic bases such as guanidine, triethylamine, pyridine, N-methyl morpholine and the like or mixtures thereof.The reaction may be carried out in the presence of solvents such as THF,dioxane, DMF, DMSO, DME, toluene, benzene, acetone, dimethyl acetamide,acetonitrile and the like or mixtures thereof. Phase transfer catalystsuch as tetraalkylammonium halides or hydroxides may be employed. Thereaction temperature may range from 0° C. to 150° C., preferably at atemperature in the range of 10° C. to 120° C. When L¹ represents,hydroxy group, the reaction may be also be carried out using Mitsunobuconditions using reagents lie DEAD, DIAD and the like.

According to yet another embodiment of the present invention, thecompound of the general formula (I) where Y represents oxygen and Wrepresents —O-aryl-(CR¹⁰R¹¹)O—NR¹²—; and all other symbols are asdefined above may be prepared by a process which comprises: reacting thecompound of formula (IIIi)

where n and p are integers ranging from 0-6, G¹ represents NH₂ or formyland all other symbols are as defined above with compound of formula(IIIh)

where q is an integer ranging from 1-6, G² represent NH₂ or formyl andall other symbols are as defined above using solvents such as CH₂Cl₂,CHCl₃, chlorobenzene, benzene, THF, in the presence of catalyst such asp-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF₃-OEt₂ andthe like. The reaction may also be carried out using activated molecularsieves. The temperature of the reaction may range from 10° C. to 100°C., preferably at a temperature in the range from 10° C. to 60° C. Theimine product initially produce may be reducing using Na(CN)BH₃—HCl(ref: Hutchins, R. O. et al. J. Org. Chem. 1983, vol. 48, 3433-3428),H2-Pd/C, H₂-Pt/C, H₂-Ph/C and the like in solvents such as methanol,ethanol and the like.

The compound of formula (I) where R⁸ represents hydrogen atom may beprepared by hydrolysing, using conventional methods, a compound offormula (I) where R⁸ represents all groups defined earlier excludinghydrogen. The hydrolysis may be carried out in the presence of a basesuch as Na₂CO₃ and a suitable solvent such as methanol, ethanol and thelike or mixtures thereof. The reaction may be carried out at atemperature in the range of 20° C.-40° C., preferably at 25° C.-30° C.The reaction time may range from 2 to 12 h, preferably from 4 to 8 h.

The compound of general formula (I) where Y represents oxygen and R⁸represents hydrogen or lower alkyl group may be converted to compound offormula (I), where Y represents NR⁹ by reaction with appropriate aminesof the formula NHR⁸R⁹, where R⁸ and R⁹ are as defined earlier to yield acompound of formula (I) where Y represents NR⁹ and all other symbols areas defined earlier. Alternatively, the compound of formula (I) where YR⁸represents OH may be converted to acid halide, preferably YR⁸═Cl, byreacting with appropriate reagents such as oxalyl chloride, thionylchloride and the like, followed by treatment with amines of the formulaNHR⁸R⁹ where R⁸ and R⁹ are as defined earlier. Alternatively, mixedanhydrides may be prepared from compound of formula (I) where YR⁸represents OH and all other symbols are as defined earlier by treatingwith acid halides such acetyl chloride, acetyl bromide, pivaloylchloride, dichlorobenzoyl chloride and the like. The reaction may becarried out in the presence of suitable base such as pyridine,triethylamine, diisopropyl ethylamine and the like. Solvents such ashalogenated hydrocarbons like CHCl₃ or CH₂Cl₂; hydrocarbons such asbenzene, toluene, xylene and the like may be used. The reaction may becarried out at a temperature in the range of −40° C. to 40° C.,preferably at a temperature in the range of 0° C. to 20° C. The acidhalide or mixed anhydride thus prepared may further be treated withappropriate amines of the formula NHR⁸R⁹ where R⁸ and R⁹ are as definedearlier to yield a compound of formula (I) where Y represents NR⁹ andall other symbols are as defined earlier.

In still another embodiment of the present invention the novelintermediate of formula (IIIb)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their salts, their solvates wherein W represents NR¹²,R¹² represents hydrogen, R¹⁰ and R¹¹ may be same or different andrepresent hydrogen or substituted or unsubstituted group selected formalkyl, alkoxy, aryl or aralkyl group; Ar represents substituted orunsubstituted divalent single or fused aromatic or heterocyclic group;R⁵ represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R⁶; R⁶ represents hydrogen, hydroxy, alkoxy, halogen,lower alkyl group, acyl, substituted or unsubstituted aralkyl or R⁶forms a bond together with R⁵; R⁷ may be hydrogen or substituted orunsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups;R⁸ may be hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Y represents oxygen, sulfur or NR¹³, where R¹³represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, orheteroaralkyl groups; R⁸ and R¹³ together may form a substituted orunsubstituted 5 or 6 membered cyclic structure containing carbon atoms,which may optionally contain one or more heteroatoms selected fromoxygen, sulfur or nitrogen, m and n are integers 0-6 is provided.

The novel intermediate of formula (IIIb) where m is 0 and all othersymbols are as defined above may be prepared by reducing the compound offormula (IIIj)

where R⁷, R⁸ and Ar are as defined above in the presence of gaseoushydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and thelike. Mixtures of catalysts may be used. The reaction may also beconducted in the presence of solvents such as dioxane, acetic acid,ethyl acetate and the like. A pressure between atmospheric pressure and80 psi may be employed. The catalyst may be preferably 5-10% Pd/C andthe amount of catalyst used may range from 1-50% w/w. The reaction mayalso be carried out by employing metal solvent reduction such asmagnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol,preferably methanol. The hydrogenation may be carried out in thepresence if metal catalysts containing chiral ligands to obtain compoundof formula (I) in optically active form. The metal catalyst may containRhodium, Ruthenium, Indium and the like. The chiral ligands maypreferably be chiral phosphines such as(2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane,1,2-bis(2-methoxyphenylphenylphosphino)ethane,(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butaneand the like. (Ref: Principles of Asymmetric Synthesis, Tet. Org. Chem.Series Vol 14, pp311-316, Pd. Baldwin J. E.).

The compound of formula (IIIj) may be prepared by reacting the compoundof formula (IIIm)O₂N—Ar—CHO   (IIIm)where Ar is as defined above with compound of formula (IIIf)

where R¹³ represents (C₁-C₆)alkyl group and all other symbols are asdefined earlier in the presence of a base such as metal hydride such asNaH or KH; organolithiums such as CH₃Li, BuLi and the like; alkoxidessuch as NaOMe, NaOEt, t-BuO⁻K⁺ and the like or mixtures thereof. Thereaction may be carried out in the presence of solvents such as diethylether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like ormixtures thereof. HMPA may be used as cosolvent. The reactiontemperature may range from −78° C. to 50° C., preferably at atemperature in the range of −10° C. to 30° C. The reaction is moreeffective under anhydrous conditions. The compound of general formula(III b) may be prepared according to the procedure described in theliterature (Annalen. Chemie, (1996) 53, 699).

In yet another embodiment of the present invention, the compound offormula (IIIb) where m is 0 and all other symbols are as defined abovemay be prepared by diazotizing the compound of formula (IIIk) to acompound of formula (IIIl) and reducing the compound of formula (IIIl)to yield compound of formula (IIIb). The reaction shown in scheme-IIIbelow:

The diazotiaziaon of the compound of the formula (IIIk)to obtaincompound of formula (IIIl) may be carried out using diazotizing agentsuch as sodium nitrite, isoamyl nitrate, potassium nitrite, ammoniumnitrite and the like under acidic conditions using acids such assulfuric acid, HCl, acetic acid and the like, in an organic solvent suchas alcohols such as methanol, ethanol, propanol and the like;1,4-dioxane, THF, acetone and the like. Etherifying the resiude usingalkyl sulfates such as diethyl sulphate, dimethylsulphate and the likeor alkyl halides such as ethyl iodide, methyliodide and the like, in thepresence of solvents such as hydrocarbons like toluene, benzene and thelike or DMF, DMSO, acetonitrile, THF, methyl isobutyl ketone (MIBK) andthe like, in alkali bases such as sodium carbonate, potassium carbonate,sodium methoxide, sodium hydride, potassium hydride and the like.

The reduction of compound of the formula (IIIl) to yield a compound ofthe general formula (IIIb) may be carried out in the presence of gaseoushydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and thelike. Mixtures of catalysts way be used. The reaction may also beconducted in the presence of solvents such as dioxane, acetic acid,ethyl acetate and the like. A pressure between atmospheric pressure and80 psi may be employed. The catalyst may be preferably 5-10% Pd/C andthe amount of catalyst used may rage from 1-50% w/w. The reaction mayalso be carried out by employing metal solvent reduction such as,magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol,preferably methanol. The hydrogenation may be carried out in thepresence of metal catalysts containing chiral ligands to obtain acompound of formula (I) in optically active form. The metal catalyst maycontain Rhodium, Ruthenium, Indium and the like. The chiral ligands maypreferably be chiral phosphines such as(2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane,1,2-bis(2-methoxyphenyl phenylphosphino)ethane,(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butaneand the like. (Ref: Principles of Asymmetric Synthesis, Tet. Org. Chem.Series Vol 14, pp311-316, Ed. Baldwin J. E.).

In yet another embodiment of the present invention, the compound offormula (IIIb) where m is 1-6, and all other symbols are as definedabove may be prepared by following the process described in scheme-IVbelow:

The reaction of a compound of the general formula (IIIf) defined abovewith a compound of formula (IIIn), to yield compound of formula (IIIo)may be carried out in the presence of a base such as metal hydride likeNaH or KH; organolithiums such as CH₃Li, BuLi and the like; alkoxidessuch as NaOMe, NaOEt, t-BuO⁻K⁺ and the like or mixtures thereof. Thereaction may be carried out in the presence of solvents such as diethylether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like ormixtures thereof. HMPA may be used as cosolvent The reaction temperaturemay range from −78° C. to 50° C., preferably at a temperature in therange of −10° C. to 30° C.

The reduction of compound of the formula (IIIo) to yield a compound ofthe formula (IIIp) may be carried out in the presence of gaseoushydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and thelike. Mixtures of catalysts may be used. The reaction may also beconducted in the presence of solvents such as dioxane, acetic acid,ethyl acetate and the like. A pressure between atmospheric pressure and80 psi may be employed. The catalyst may be preferably 5-10% Pd/C andthe amount of catalyst used may range from 1-50% w/w. The reaction mayalso be carried out by employing metal solvent reduction such asmagnesium, iron, tin, samarium in alcohol or sodium in alcohol,preferably methanol. The hydrogenation may be carried out in thepresence off catalysts containing chiral ligands to obtain a compound offormula (I) in optically active form. The metal catalyst may containRhodium, Ruthenium, Indium and the like. The chiral ligands maypreferably be chiral phosphines such as(2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane,1,2-bis(2-methoxyphenyl phenylphosphino)ethane(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butaneand the like.

The reaction of a compound of general formula (IIIp) with a compound offormula. (IIIq) may be carried out using solvents such as CH₂Cl₂, CHCl₃,chlorobenzene, benzene, THF, in the presence of catalyst such asp-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF₃-OEt₂ andthe like. The reaction may also be carried out using activated molecularsieves. The temperature of the reaction may range from 10° C. to 100°C., preferably at a temperature in the range from 10° C. to 60° C. Theimine product initially produce may be reducing using Na(CN)BH₃—HCl(ref. Hutchins, R. O. et al. J. Org. Chem. 1983, vol. 48, 3433-3428),H2-Pd/C, H₂-Pt/C, H₂-PhC and the like in solvent such as methanol,ethanol and the like.

In yet another embodiment of the present invention, the compound offormula (IIIb) where m is 0 or 1 and all other symbols are as definedabove may be prepared by diazotizing the compound of formula (IIIk) to acompound of formula (Va), decomposition of compound of formula (Va) to acompound of formula (IIIl) m the presence of alcohol such as R⁷OH andreducing the compound of formula (IIIl) to yield compound of formula(IIIb). The reaction sequence is shown in scheme-V below:

The diazotiaziaon of the compound of the formula (IIIk) where m is 0, R⁶is hydrogen and all other symbols are as defined above, to obtaincompound of formula (Va) may be carried out using diazotizing agent suchas sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitriteand the like in the presence of catalytic amount of carboxylic acid suchas acetic acid, propionic acid and the like, in suitable solvent such aschloroform, chlorobenzene, dichloroethane and the like or a mixturethereof at a temperature in the range of room temperature and refluxtemperature of the solvent employed for a period in the range of 0.5 to16 h.

Decomposing the arylalkyl diazo acetate of the formula (Va) to obtain acompound of formula (IIIl) where R⁷ is as defined earlier excludinghydrogen and all other symbols are as defined earlier can be promoted bya suitable catalyst such as Rh(II)acetate, salt/complex of Cu(I) orRh(II) and the like (Bio. Org. Med. Chem. Lett., 1996, 2121-2126) in thepresence of an alcohol of the formula R⁷OH.

The reduction of compound of the formula (IIIl) to yield a compound ofthe general formula (IIIb) where all symbols are as defined earlier maybe carried out in the presence of gaseous hydrogen and a catalyst suchas Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalystsmay be used. The reaction may also be conducted in the presence ofsolvents such as dioxane, acetic acid, ethyl acetate and the like. Apressure between atmospheric pressure and 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 1-50% w/w. The reaction may also be carried out byemploying metal solvent reduction such as magnesium, iron, tin, samariumin alcohol or sodium amalgam in alcohol; preferably methanol. Thehydrogenation may also be carried out using ammonium formate,cyclohex-1,4-diene type of hydrogen donor under pd/c conditions usingsolvents such as methanol, ethanol, ethyl acetate and the like.

In yet another embodiment of the present invention, the compound offormula (IIIb) in its enantiomerically pure form, where m is 0, R⁵═R⁶═Hand all other symbols are as defined above may be prepared by followingthe process described in scheme-VI below:

The diazotization of the compound of the formula (VIa) where all symbolsare as defined above to obtain compound of formula (VIb) may be carriedout by using diazotizing agent such as sodium nitrite, isoamyl nitrite,potassium nitrite, ammonium nitrite and the like under aqueous acidicconditions using acids such as sulfuric acid, HCl, acetic acid and thelike, in a organic solvent such as alcohols such as methanol, ethanol,propanol and the like; 1,4-dioxane, THF, acetone and the like.

One pot esterification and etherification of compound of general formula(VIb) to a compound of general formula (VIc) may be carried by initialdi deprotonation of (VIb) using a suitable base such as NaH, KH, KOH orlike, in a suitable solvent such as toluene, benzene, diethylether, THF,DMF, DME HMPA, and like, followed by treatment with alkyl halide such asethyl iodide or methyl iodide and like. Other alkylating agents such asEt₃O+BF₄ ⁻; Me₃O⁺BF₄ ⁻, dialkylsulfate may also be used. Reactiontemperature may vary from 0° C. to 100° C.

Nitration of the compound of formula (VIc) to a compound of formula(VId) where n is 0 and all other symbols are as defined above, may becarried out using nitrating agents such as fuming nitric acid, N₂O₅, amixture of conc. Nitric acid and conc. Sulfuric acid or a mixture ofnitric acid and acetic anhydride in the presence of a solvent or underneat condition at a temperature in the range of −10° C. to roomtemperature for a period in the range of 0.5 to 4 h. (Ref Org. Synth.Col. Vol. I, 396)

Reduction of compound of the formula (VId) to a compound of formula(IIIb), may be carried out in the presence of gaseous hydrogen orhydrogen donors such as ammonium formate, cyclohex-1,4-diene and thelike and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like.Mixtures of catalysts may be used in the presence of solvents such asmethanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Apressure between atmospheric pressure and 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 1-50 % w/w. Alternatively, the reaction may also becarried out by employing metal solvent reduction such as magnesium,iron, tin, samarium, indium, sodium amalgam in alcohol, or othersuitable solvents preferably methanol.

In yet another embodiment of the present invention, the compound offormula (IIIb) in its enantiomerically pure form, where m is 0, R⁵═R⁶═Hand all other symbols are as defined above may be prepared by followingthe process described in scheme-VII below:

The diazotization of the compound of formula (VIIa) where all symbolsare as defined above to obtain a compound of formula (VIIb) may becarried out using diazotizing agents such as sodium nitrite, isoamylnitrite, potassium nitrite, ammonium nitrite and the like under acidaqueous acidic conditions using acids such as sulfuric acid,hydrochloric acid, acetic acid and the like, in presence of an optionalco solvent like alcohols such as methanol, propanol, and the like; orethers such as 1,4-dioxane, THF, and the like; or ketones such asacetone, methyl ethyl ketone and the like.

Esterification of the compound of formula (VIIb) to a compound offormula (VIIc) may be done using an appropriate alcohol of formula R⁸—OHwhere R⁸ represents lower alkyl groups such as methyl, ethyl, propyl,isopropyl, n-butyl, t-butyl and the like in presence of suitablecatalyst such as, conc. sulfuric acid, dry HCl, BF₃—OEt₂, and the like.The reaction may be carried out at reflux temperature of the alcoholemployed. Alternatively reagents like diazomethane or Et₃O⁺BF₄ ⁻ orMe₃O⁺B₄ ⁻ and the like may also be used for esterification.

Selective O-alkylation of the compound of formula (VIIc) to the compoundof formula (VIId) may be done using alkyl sulfates such as diethylsulfate, dimethyl sulfate and the like or alkyl halides such as ethyliodide, methyl iodide, n-propyl iodide, n-propyl bromide, isopropyliodide and the like, in solvents such as hydrocarbons like toluene,benzene and the like or acetonitrile, tetrahydro furan, dimethylformamide, dimethyl sulfoxide, and the like, in the presence ofmolecular sieves and alkali bases such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium methoxide, sodium hydride, potassiumhydride, sodium or potassium hydroxide and the like. Heavy metal oxidessuch as Ag₂O, PbO, HgO and the like may be of particular use to carryout alkylation when alkyl halides are used as alkylation reagent. Phasetransfer catalysts such as tetraalkylammonium hydroxide ortetraalkylammonium halides such as tetrabutylammonium chloride,tetrabutylammonium bromide and the like may also be employed.

Reduction of compound of the formula (VIId) to a compound of formula(IIIb), may be carried out in the presence of gaseous hydrogen orhydrogen donors such as ammonium formate, cyclohex-1,4-diene and thelike and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like.Mixtures of catalysts may be used in the presence of solvents such asmethanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Apressure between atmospheric pressure and 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 1-50% w/w. Alternatively, the reaction may also becarried out by employing metal solvent reduction such as magnesium,iron, tin, samarium, indium, sodium amalgam in alcohol, or othersuitable solvents preferably methanol.

In yet another embodiment of the present invention, the compound offormula (IIIb) in its enantiomerically pure form, where m is 0, R⁵═R⁶═Hand all other symbols are as defined above may be prepared by followingthe process described in scheme-VIII below:

The diazotization of the compound of formula (VIIa) where all symbolsare as defined above to obtain a compound of formula (VIIb) may becarried out using diazotizing agents such as sodium nitrate, isoamylnitrite, potassium nitrite, ammonium nitrite and the like under aqueousacidic conditions using acids such as sulfuric acid, hydrochloric acid,acetic acid and the like, in presence of an optional co solvent likealcohols such as methanol, ethanol, propanol and the like; or etherssuch as 1,4-dioxane, THF, and the like; or ketones such as acetone,methyl ethyl ketone and the like.

Esterification of the compound of formula (VIIb) to a compound offormula (VIIc) may be done using an appropriate alcohol of formula R⁸—OHwhere R⁸ represents lower alkyl groups such as methyl, ethyl, propyl,isopropyl, n-butyl, t-butyl and the like in presence of suitablecatalyst such as, conc. sulfuric acid, dry HCl, BF₃—OEt₂, and the like.The reaction may be carried out at reflux temperature of the alcoholemployed. Alternatively reagents like diazomethane or Et₃O⁺BF₄ ⁻ orMe₃O⁺BF₄ ⁻ and the like may also be used for esterification.

Reduction of compound of the formula (VIIc) to a compound of formula(VIIIa), may be carried out in the presence of gaseous hydrogen orhydrogen donors such as ammonium formate, cyclohex-1,4-diene and thelike and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like.Mixture of catalysts may be used in the presence of solvents such asmethanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Apressure between atmospheric pressure to 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 1-50% w/w. Alternatively, the reaction may also becarried out by employing metal solvent reduction such as magnesium,iron, tin, samarium, indium, sodium amalgam in alcohol, or othersuitable solvents preferably methanol.

N,N-dibenzylation of the compound of formula (VIIIa) to the compound offormula (VIIIb) may be done using benzyl halides such as benzyl bromide,benzyl chloride and the like in solvents such as hydrocarbons liketoluene, benzene and the like or acetonitrile, tetrahydro furan,dimethyl formamide, dimethyl sulfoxide, and the like, in the presence ofalkali bases such as sodium carbonate, potassium carbonate, sodium orpotassium hydroxide and the like. Phase transfer catalysts such astetraalkylammonium hydroxide or tetraalkylammonium halides such astetrabutylammonium chloride, tetrabutylammonium bromide and the like mayalso be employed. The reaction may be carried out in the range of roomtemperature to the reflux temperature of the solvent employed.

Hydrolysis of the compound of the formula (VIIIb) to the compound offormula (VIIIc) using aqueous alkali metal bases such as lithiumcarbonate, sodium carbonate, potassium carbonate or potassiumbicarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxideand the like, in suitable co-solvents such as methanol, ethanol, THF andlike or mixtures thereof. The reaction time may range from 0.5 h to 24h, preferably 0.5 h to 3-4 h and reaction temperature may range from 0°C. to 80° C.

One pot esterification and etherification of the compound of the formula(VIIIc) to the compound of formula (VIIId) where R⁵═R⁶, may be done bytreating with bases such as sodium hydride, potassium hydride, sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonateand the like, in solvents such as hydrocarbons like toluene, benzene andthe like, dialkyl ethers such as diethyl ether, tetrahydro furan and thelike or dimethyl formamide, HMPA followed by treatment with alkylhalides such as ethyl iodide, methyl iodide, n-propyl iodide, n-propylbromide, isopropyl iodide and the like, or alkyl sulfates such asdiethyl sulfate, dimethyl sulfate and the like or alkylating agents suchas Et₃O⁺BF₄ ⁻, Me₃O⁺BF₄ ⁻ and the like. The reaction time may range from2 h to 20 h and reaction temperature may range from 0° C. to 80° C.

Debenzylation of the compound of the formula (VIIId) to the compound offormula (IIIb) may be carried out in the presence of gaseous hydrogen orhydrogen donors such as ammonium formate, cyclohex-1,4-diene and thelike and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like.Mixture of catalysts may be used in the presence of solvents such asmethanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Apressure between atmospheric pressure and 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 1-50% w/w.

The novel intermediate of formula (IIIb) where W represents NR¹² and R¹²represents hydrogen that can be used to prepare the compounds of thepresent invention and process for preparing the intermediate (IIIb) isdescribed and claimed in our PCT application entitled “Novelβ-phenyl-α-oxysubstituted propionic derivatives: process for itspreparation and their use in the preparation of pharmaceuticallyimportant compounds.” filed on the same day as this application.

In still another embodiment of the present invention the novelintermediate of formula (IIId)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically accept solvates wherein L¹ is a leavinggroup such as halogen atom, methanesulfonate, trifluoromethanesulfonate,p-toluenesulfonate, p-nitrobenznensulfonate, acetate, sulfate, phosphateor hydroxy; W represents NR¹², —C(═O)—(CR¹⁰R¹¹)_(o)—NR¹²,—O-aryl-(CR¹⁰R¹¹)_(o)—NR¹², where R¹² represents hydrogen or substitutedor unsubstituted group selected from alkyl, aryl or aralkyl groups; o isan integer ranging from 0-4; R¹⁰ and R¹¹ may be same or different andrepresent hydrangea or unsubstituted or unsubstituted group selectedform alkyl, alkoxy, aryl or aralkyl group; Ar represents substituted orunsubstituted divalent single or fused aromatic or heterocyclic group;R⁵ represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R⁶; R⁶ represents hydrogen, hydroxy, alkoxy, halogen,lower alkyl group, acyl, substituted or unsubstituted aralkyl or R⁶forms a bond together with R⁵; R⁷ may be hydrogen or substituted orunsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups;R⁸ may be hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl heterocyclyl, heteroaryl orheteroaralkyl groups; Y represents oxygen, sulfur or NR⁹, where R⁹represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, orheteroaralkyl groups; R⁸ and R⁹ together may form a substituted orunsubstituted 5 or 6 membered cyclic structure containing carbon atoms,which may optionally contain one or more heteroatoms selected fromoxygen, sulfur or nitrogen; m and n are integers ranging from 0-6 isprovided.

In yet another embodiment of the present invention the novelintermediate of formula (IIIg)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates wherein R¹, R² and R³,R⁴ when attached to the carbon atom, may be same or different andrepresent hydrogen, halogen, hydroxy, nitro, cyano, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteoaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or is derivatives, or sulfonic acid or its derivatives;one or both of R³ and R⁴ may represent oxo or thioxo group when they areattached to carbon atom; R³ and R⁴ when attached to nitrogen atomrepresent hydrogen, hydroxy, formyl or optionally substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino,aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylicacid derivatives, or sulfonic acid derivatives; X represents aheteroatom selected from oxygen or sulfur, R¹⁰ and R¹¹ may be same ordifferent and represent hydrogen or substituted or unsubstituted groupselected form alkyl, alkoxy, aryl or aralkyl group; L¹ is a leavinggroup such as halogen atom, methanesulfonate, trifluoromethanesulfonate,p-toluenesulfonate, p-nitrobenznensulfonate, acetate, sulfate, phosphateor hydroxy; n and o are integer ranging from 0-6 is provided.

In yet another embodiment of the present invention the novelintermediate of formula (IIIi)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates wherein R¹, R² and R³,R⁴ when attached to the carbon atom, may be same or different andrepresent hydrogen, halogen, hydroxy, nitro, cyano, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R³ and R⁴ may represent oxo or thioxo group when they areattached to carbon atom; R³ and R⁴ when attached to nitrogen atomrepresent hydrogen, hydroxy, formyl or optionally substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino,aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylicacid derivatives, or sulfonic acid derivatives; X represents aheteroatom selected from oxygen or sulfur, R¹⁰ and R¹¹ may be same ordifferent and represent hydrogen or substituted or unsubstituted groupselected form alkyl, alkoxy, aryl or aralkyl group; G¹ is CHO or NH₂ isprovided, n and p are integer ranging from 0-6.

It is appreciated that in any of the above mentioned reactions, anyreactive group in the substrate molecule may be protected according toconventional chemical practice. Suitable protecting groups in any of theabove mentioned reactions are tertiarybutyl dimethyl silylchloride,methoxymethyl chloride etc, to protect hydroxyl group, N-Boc, N-Cbz,N-Fmoc etc, for protection of amino group, acetal protection foraldehyde, ketal protection for ketone and the like. The methods offormation and removal of such protecting groups are those conventionalmethods appropriate to the molecule being protected.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula (I) with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium hydroxide,potassium t-butoxide, calcium hydroxide, magnesium hydroxide and thelike, in solvents like ether, THF, methanol t-butanol, dioxane,isopropanol, ethanol, toluene etc. Mixtures of solvents may be used.Organic bases like lysine, arginine, diethanolamine, choline, guanidine,adamentyl amine and their derivatives etc. may also be used.Alternatively, acid addition salts wherever applicable are prepared bytreatment with acids such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid,methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylicacid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinicacid, benzoic acid, bezenesulfonic acid, tartaric acid and the like insolvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane acidthe like. Mixtures of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are complied by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula (I) where YR⁸represents OH may be converted to a 1:1 mixture of diastereomeric amidesby treating with chiral amines, amino acids, amino alcohols derived fromaminoacids; conventional reaction conditions may be employed to convertacid into an amide; the diastereomers may be separated either byfractional crystallization or chromatography and the stereoisomers ofcompound of formula (I) may be prepared by hydrolyzing the purediastereomeric amide.

Pharmaceutically acceptable solvates of the compounds of formula (I)forming part of this invention may be prepared by conventional methodssuch as dissolving the compound of formula (I) in solvents such aswater, methanol, ethanol and the like, preferably water andrecrystallizing by using different crystallization techniques.

Various polymorphs of a compound of general formula (I) forming part ofthis invention may be prepared by crystallization of compound of formula(I) under different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the lo compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe NMR spectroscopy, IR spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

The present invention provides a pharmaceutical composition, containingthe compounds of the general formula (I) as defined above, theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their pharmaceutically acceptable salts or theirpharmaceutically acceptable solvates in combination with the usualpharmaceutically employed carriers, diluents and the like, useful forthe treatment and/or prophylaxis of diseases such as hypertension,coronary heart disease, atherosclerosis, stroke, peripheral vasculardiseases and related disorders. These compounds are useful for thetreatment of hyperlipidemia, hyperglycemia, familialhypercholesterolemia, hypertriglyceridemia, lowering of atherogeniclipoproteins, VLDL and LDL. The compounds of the present invention canbe used for the treatment of certain renal diseases includingglomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis, nephropathy. The compounds of general formula (I) arealso useful for the treatment/prophylaxis of insulin resistance (type IIdiabetes), leptin resistance, impaired glucose tolerance, dyslipidemia,disorders related to syndrome X such as hypertension, obesity, insulinresistance, coronary heart disease, and other cardiovascular disorders.These compounds may also be useful as aldose reductase inhibitors, forimproving cognitive functions in dementia, treating diabeticcomplications, disorders related to endothelial cell activation,psoriasis, polycystic ovarian syndrome (PCOS), inflammatory boweldiseases, osteoporosis, myotonic dystrophy, pancreatitis, retinopathy,arteriosclerosis, xanthoma, inflamation and for the treatment of cancer.The compounds of the present invention are useful in the treatmentand/or prophylaxis of the above said diseases incombination/concomittant with one or more HMG CoA reductase inhibitors;cholesterol absorption inhibitors; antiobesity drugs; lipoproteindisorder treatment drugs; hypoglycemic agents: insulin; biguanides;sulfonylureas; thiazolidinediones; dual PPARα and γ or a mixturethereof. The compounds of the present invention combination with HMG CoAreductase inhibitors, cholesterol absorption inhibitors, antiobesitydrugs, hypoglycemic agents can be administered together or within such aperiod to act synergistically.

The present invention also provides a pharmaceutical composition,containing the compounds of the general formula (I) as defined above,their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptable saltsor their pharmaceutically acceptable solvates and one or more HMG CoAreductase inhibitors; cholesterol absorption inhibitors; antiobesitydrugs; lipoprotein disorder treatment drugs; hypoglycemic agents:insulin; biguanides; sulfonylureas; thiazolidinediones; dual PPARα and γor a mixture thereof in combination with the usual pharmaceuticallyemployed carriers, diluents and the like.

The pharmaceutical composition may be in the forms normally employed,such as tablets, capsules, powders, syrups solutions, suspensions andthe like, may contain flavorants, sweeteners etc. in suitable solid orliquid carries or diluents, or in suitable sterile media to forminjectable solutions or suspensions. Such compositions typically containfrom 1 to 20%, prefetably 1 to 10% by weight of active compound, theremainder of the composition being pharmaceutically acceptable carriers,diluents or solvents.

Suitable pharmaceutically acceptable carriers include solid fillers ordiluents and sterile aqueous or organic solutions. The active ingredientwill be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the compound of formula (I) can becombined with a suitable solid or liquid carrier or diluent to formcapsules, tablets, powders, syrups, solutions, suspensions and the like.The pharmaceutical compositions, may, if desired, contain additionalcomponents such as flavourants, sweeteners, excipients and the like. Forparenteral administration, the polymorphic form can be combined withsterile aqueous or organic media to form injectable solutions orsuspensions. For example, solutions in sesame or peanut oil, aqueouspropylene glycol and the like can be used, as well as aqueous solutionsof water-soluble pharmaceutically-acceptable acid addition salts orsalts with base of the compounds. Aqueous solutions with the activeingredient dissolved in polyhydroxylated castor oil may also be used forinjectable solutions. The injectable solutions prepared in this mannercan then be administered intravenously, intraperitoneally,subcutaneously, or intramuscularly, with intramuscular administrationbeing preferred in humans.

For nasal administration, the preparation may contain the polymorphicforms of the present invention dissolved or suspended in a liquidcarrier, in particular an aqueous carrier, for aerosol application. Thecarrier may contain additives such as solubilizing agents, such aspropylene glycol, surfactants, absorption enhancers such as lecithin(phosphatidylcholine) or cyclodextrin or preservatives such asparabenes.

Tablets, dragees or capsules having talc and/or a carbohydrate carriedbinder or the like are particularly suitable for any oral application.Preferably, carriers for tablets, dragees or capsules include lactose,corn starch and/or potato starch. A syrup or elixir can be used in caseswhere a sweetened vehicle can be employed.

A typical tablet production method is exemplified below: TabletProduction Example a) 1) Active ingredient  30 g 2) Lactose  95 g 3)Corn starch  30 g 4) Carboxymethyl cellulose  44 g 5) Magnesium stearate 1 g 200 g for 1000 tablets

The ingredients 1 to 3 are uniformly blended with water and granulatedafter drying under reduced pressure. The ingredients 4 and 5 are mixedwell with the granules and compressed by a tabletting machine to prepare1000 tablets each containing 30 mg of active ingredient. a) 1) Activeingredient   30 g 2) Calcium phosphate   90 g 3) Lactose   40 g 4) Cornstarch   35 g 5) Polyvinyl pyrrolidone  3.5 g 5) Magnesium stearate  1.5g  200 g for 1000 tablets

The ingredients 1 to 4 are uniformly moistened with an aqueous solutionof 5 and granulated after drying under reduced pressure. Ingredient 6 isadded and granules are compressed by a tabletting machine to prepare1000 tablets containing 30 mg of ingredient 1.

The compound of formula (I) defined above are clinically administered tomammals, including man, via either oral, nasal, pulmonary, transdermalor parental, rectal, depot, subcutaneous, intravenous, intrauretheral,intramuscular, intranasal, ophthalmic solution or ointment.Administration by the oral route is preferred, being more convenient andavoiding the possible pain and irritation of injection. However, incircumstances where the patient cannot swallow the medication, orabsorption following oral administeration is impaired, as by disease orother abnormality, it is essential that the drug be administeredparenterally. By either route, the dosage is in the range of about 0.01to about 100 mg/kg body weight of the subject per day or preferablyabout 0.01 to about 30 mg/kg body weight per day administered singly oras divided dose. However, the optimum dosage for the individual subjectbeing treated will be determined by the person responsible fortreatment, generally smaller doses being administered initially andthereafter increments made to determine the most suitable dose.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

Preparation 1 Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate

Step (i)

Wittig salt from triethyl 2-ethoxyphosphonoacetate (26.5 g, 1.5 eq, 99.3mmol) and NaH (50% in oil) (5.3 g, 2 eq, 132.4 mmol) was prepared in THF(350 ml) at 0° C. To this solid 4-nitrobenzaldehyde (10 g, 1 eq, 66.2mmol) was added in portions at 0° C. and the resulting solution wasstirred at RT for 16 h. The reaction mixture was diluted with ethylacetate and washed with aqueous NH₄Cl. The crude contains ethyl4-nitro-2-ethoxycinnamate in both Z and E stereoisomers (11 g).

Step (ii)

Ethyl 4-nitro-2-ethoxycinnamate obtained in step (i) was hydrogenatedusing Pd (10%)/C—H₂ (60 psi) (11 g) in ethyl acetate (150 ml) at RT andchromatographed using ethyl acetate/hexane to yield the title compoundas viscous oil (9.41 g, yield 60%).

¹H NMR (200 MHz, CDCl₃) δ: 1.16 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.0 Hz,3H), 2.90 (d, J=6.3 Hz, 2H), 3.30 (bs, 2H, NH₂), 3.35 (m, 1H), 3.55 (m,1H), 3.94 (t, J=6.3 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 6.62 (d, J=8.3 Hz,2H), 7.03 (d, J=8.0 Hz, 2H).

IR (neat) cm⁻¹: 3372, 1738.

Mass m/z (CI): 238 (M+1), 192 (M-OC₂H₅).

Preparation 2 3-(3,4Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide

A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (3.0 g, 1 eq, 22.2mmol), 1,3-dibromopropane (22.5 ml, 10 eq, 222 mmol) and anhydroussodium carbonate (7.05 g, 3 eq, 66.6 mmol) in dry DMF (200 ml) washeated at 70° C. for 16 h. The reaction mixture was diluted with ethylacetate and washed with water and brine. The residue was chromatographedusing ethyl acetate and hexane to yield the title compounds as liquidmass (2.6 g, 47%).

¹H NMR (200 MHz, CDCl₃) δ: 2.10-2.30 (m, 2H), 3.37 (t, J=4.4 Hz, 2H)3.40-3.56 (m, 4H), 4.25 (t, J=4.3 Hz, 2H), 6.60-6.90 (m aromatics, 4H).

Mass m/z (CI): 255 (M(⁷⁹Br)), 256 (M(⁷⁹Br)+1), 257 (M(Br⁸¹)), 258(M(Br⁸¹)+1).

Preparation 3 Ethyl 2ethoxy-3-[4-{N-heptyl-N-(2′-aminophenyl]propanoate

Step (i)

A mixture of ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (5 g, 1 eq, 21mmol) obtained in preparation 1, heptylbromide (18.8 g, 5 eq, 105 mmol),and anhydrous K₂CO₃ (14.5 g, 5 eq, 105 mmol), was heated at 70° C. inDMF (100 ml), for 16 h. The reaction mixture was diluted with ethylacetate, washed with water and brine. The residue was chromatographedusing a mixture of ethyl acetate and hexane as diluent to affordmonoheptylated product as thick liquid (3.85 gm, yield 55%).

¹H NMR (200 MHz, CDCl₃) δ: 0.88 (bt, J=6.3 Hz, 3H), 1.05-1.42 (m 15H),1.42-1.68 (m, 2H), 2.90 (d, J=6.6 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H),3.22-2.42 (m 1H), 3.44-3.64 (m, 1H), 3.94 (t, J=6.8 Hz, 1H), 4.1 (q,J=7.0 Hz, 2H), 6.55 (d, J=8.3 Hz, 2H), 7.04 (d, J=8.31 Hz, 2H).

IR (neat) cm⁻¹: 3396, 1747.

Mass m/z (CI): 335 (M+1), 290 (M-OC₂H₅).

Step (ii)

The mono heptylated product (3 g, 1 eq, 8.98 mmol) obtained in step (i)was treated with excess dibromoethane (10 eq) in presence of anhydrousK₂CO₃ (3.72 g, 3 eq, 27 mmol), in DMF (40 ml), and heated at 70° C. for16 h. The reaction mixture was diluted with ethyl acetate, washed withwater and brine. The residue was chromatographed using a mixture ofethyl acetate and hexane as diluent to yield ethyl2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate asthick liquid (1.98 g, yield 50%).

¹H NMR (200 MHz, CDCl₃) δ: 0.88 (bt, J=6.3 Hz, 3H), 1.05-1.42 (m, 14H),1.42-1.68 (m, 2H), 2.90 (d, J=6.6 Hz, 2H), 3.28 (t, J=7.3 Hz, 2H),3.30-3.45 (m, 3H), 3.50-3.70 (m, 3H), 3.96 (t, J=6.8 Hz, 1H), 4.17 (q,J=7.0 Hz, 2H), 6.57 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 1747.

Mass m/z (CI): 442 (M(⁷⁹Br)+1), 444 (M(Br⁸¹)+1).

Preparation 42-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)carboxymethylchloride

3,4-Dihydro-2H-benzo[b][1,4]oxazine (1.52 g, 1 eq, 11.3 mmol), triethylamine (4.73 ml, 3 eq, 33.9 mmol) and catalytic amount of DMAP was takenin dry DCM (50 ml). To this mixture 2-chloroacetyl chloride (1.8 ml, 2eq, 22.6 mmol) was added at 0° C. and the reaction mixture was stirredat 0° C. for 4 h. The reaction mixture was diluted with DCM and washedwith dil. aqueous HCl, followed by NaHCO₃ and brine. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated on rotavapor. The crudecompound was chromatographed using ethyl acetate and hexane to yield thetitle compounds as waxy solid (1.54 g, yield 65%)

¹H NMR (200 MHz, CDCl₃) δ: 3.98 (t, J=4.4 Hz, 2H), 4.25-4.40 (m, 4H),6.90-7.20 (aromatics, 4H).

IR (neat) cm⁻¹: 1655.

Mass m/z (CI): 212 (M(³⁵Cl)⁺1), 214 (M(Cl³⁷)+1).

Preparation 5 Methyl 3-[4-formylphenyl]-2-ethoxypropanoate

Step (i)

Wittig salt from triethyl 2-ethoxphosphonoacetate (25.6 g, 2.0 eq, 96mmol) and NaH (3.84 g, 2 eq, 96 mmol) was prepared in THF (240 ml) at 0°C. To this terepthalaldehyde monodiethylacetal (10 g, 1 eq, 48 mmol) wasadded dropwise at 0° C. The resulting solution was stirred at RT for 24h. The reaction mixture was diluted with ethyl acetate and washed withaqueous NH₄Cl. The residue was chromatographed (ethyl acetate andhexane) to obtain ethyl 4′-(diethoxymethyl)-2-ethoxycinnamate in both Zand E stereoisomers (13.9 g, 90% yield).

Step (ii)

A dry methanolic (20 ml) solution of ethyl4′-(diethoxymethyl)-2-ethoxycinnamate (5 g, 1 eq, 15.5 mmol), obtainedin step (i) was added to dry methanol (6 ml) containing activatedmagnesium turning (7.44 g, 20 eq, 310 mmol) and was allowed to stir.Eventually the reaction mixture becomes vigorous requiring refluxcondenser. Once the magnesium gets consumed to yield Mg(OMe)₂ (takes 3-4h), it was stirred at RT for 16 h. The reaction mixture was acidifiedcarefully with conc HCl stirred for 2 h at RT. Finally ethyl acetate wasadded and the organic layer was thoroughly washed with water and brineand dried over anhydrous Na₂SO₄. The residue was chromatographed(EtOAc/hexane) to afford the title compound as viscous oil (2.92 g,yield 80%).

¹H NMR (200 MHz, CDCl₃) δ: 1.14 (t, J=6.8 Hz, 3H), 3.00-3.20 (m, 2H),3.22-3.41 (m, 1H), 3.48-3.67 (m, 1H) 3.73 (s, 3H), 4.06 (dd, J=7.8, 5.4Hz, 1H), 6.40 (d, J=8.3 Hz, 2H), 7.81 (d, J=8.3 Hz, 2H),9.9 (s, 1H).

IR (neat) cm⁻: 1751, 1701.

Mass m/z (CI): 237 [M+1].

Preparation 6 Methyl2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate

Step (i)

Methyl 3-[4formylphenyl]-2-ethoxypropanoate (2 g, 1 eq, 8.51 mmol)obtained in preparation 5, heptylamine (978 mg, 1 eq, 8.51 mmol) andcat. amount of p-TsOH.H₂O were taken in DCM (40 ml), along with fewpieces of activated molecular sieves (4 A). The reaction mixture wasfiltered through celite after 24 h, at RT and the filtrate was dilutedwith DCM and was washed with aqueous sodium bicarbonate and dried overanhydrous sodium sulfate to yield crude methyl2-ethoxy-3-[4-(N-heptyliminomethyl)phenyl]propanoate

Step (ii)

The crude methyl 2-ethoxy-3-[4-(N-heptylimiomethyl)phenyl]propanoateobtained in step (i) above (2.95 g), was dissolved in methanol (40 ml),and treated with conc. HCl (850 μl, 1 eq, 8.51 mmol) and sodiumcyanoborohydride (535 mg, 1 eq, 8.51 mmol) at 0° C. The progress of thereaction was monitored by TLC. After 2-3 h, the reaction mixture wasdiluted with ethyl acetate, washed with aqueous sodium bicarbonate anddried over anhydrous sodium sulfate. The residue was chromatographedusing methanol and chloroform to afford the title compound (1.71 g,yield 60%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 0.86 (bt, J=6.3 Hz, 3H), 1.14 (t, J=6.8 Hz,3H), 1.20-1.40 (m, 9H), 1.50-1.70 (m, 2H), 2.60 (t, J=7.4 Hz, 2H), 2.98(d, J=6.3 Hz 2H), 3.22-3.41 (m, 1H), 3.48-3.67 (m, 1H), 3.71 (s, 3H),3.89 (s, 2H), 4.02 (t, J=6.3 Hz, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.30 (d,J=7.8 Hz, 2H).

IR (neat) cm⁻¹: 3500 (br), 1748.

Mass m/z (CI): 336 [M+1].

Preparation 7 Methyl 2-ethoxy-3-(4-aminophenyl)propanoate

Ethyl 4-nitro2-ethoxycinnamate (10 g, 1 eq, 37.7 mmol) obtained in step(i) of preparation 1, was treated with activated magnesium turnings (18g, 20 eq, 754 mmol) in dry methanol (400 ml). The reaction mixture wasrefluxed for 2-3 h, and allowed to stir at room temperature for 16 h.The reaction mixture was diluted with ethyl acetate and quenched withcold aqueous ammonium chloride. The organic layer was washed with waterand brine. The residue was chromatographed using ethyl acetate andhexane to afford the title compound as liquid (6 g, yield 72%).

¹H NMR (200 MHz, CDCl₃) δ: 1.64 (t, J=, 6.8 Hz, 3H), 2.90 (d, J=6.3 Hz,2H), 3.22-3.42 (m, 1H), 3.42-3.65 (m, 2H), 3.70 (s, 3H), 3.96 (t, J=6.8Hz, 1H), 6.61 (d, J=8.3 Hz, 2H), 7.00 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3350 (br), 1735.

Mass m/z (CI): 224 [M+1].

Preparation 8 5-(3,4Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylbromide

Step (i)

To a mixture of 5-bromo pentanoic acid (4.63 g, 1 eq, 25.6 mmol) andoxalyl chloride (11.2 ml, 5 eq, 128 mmol) in hexane (5 ml), DMF (10 μl)was added and the reaction mixture was heated at 70° C. for 3 h. Theexcess oxalyl chloride and hexane were removed by distillation and theresidue was distilled under high vacuum to yield 5-bromo pentanoylchloride as light yellow liquid (2.1 g, yield 41%).

Step (ii)

To a solution of 3,4-dihydro-2H-benzo[b]oxazine (500 mg, 1 eq, 3.7mmol), triethylamine (1.54. ml, 3 eq, 11.1 mmol) and catalytic amount ofDMAP in dry DCM (20 ml) was added 5-bromo pentanoyl chloride (870 μl, 2eq, 7.40 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 4h and then diluted with excess ethyl acetate. The ethyl acetate layerwas washed with dil. HCl, water and then with brine. The residue waschromatographed with ethyl acetate and hexane to yield the titlecompound liquid (535 mg, yield 53%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.70- 2.00 (m, 4H), 2.63 (bt, J=5.9 Hz, 2H),3.39 (t, J=5.8 Hz, major rotamer 1.2H), 3.53 (t, J=6.3 Hz, minor rotamer0.8H), 3.94 (t, J=4.4 Hz, 21H), 4.29 (t, J=4.9 Hz, 2H), 6.80-7.20(aromatics, 4H).

IR (neat) cm⁻¹: 2936, 1660.

Mass m/z (CI): 298 [M(⁷⁹Br)+1], 300 [M(⁸¹Br)+1].

Preparation 9 Methyl 2-ethoxy-3-(3-aminophenyl)propanoate

Step (i)

Wittig salt from triethyl 2-ethoxyphosphonoacetate (34.3 ml, 2 eq, 132mmol) and NaH (50% in oil) (6.28 g, 2 eq, 132 mmol) was prepared in THF(350 ml) at 0° C. To this solid 3-nitrobenzaldehyde (10 g, 1 eq, 66mmol) was added in portions at 0° C. The resulting solution was stirredat RT for 16 h. The reaction mixture was diluted with ethyl acetate andwashed with aqueous NH₄Cl. The crude contains ethyl4-nitro-2-ethoxycinnamate in both Z and E stereoisomers (15 g, yield86%).

Step (ii)

The crude compound (15 g, 1 eq, 56.6 mmol) obtained it step (i) wasdissolved in methanol (250 ml). To this ammonium formate (35.6 g, 10 eq,566 mmol) and 10% Pd/C (40 g) was added and the reaction was stirred atRT for 16 h. The catalyst was filtered and the methanol was condensed onrotavapour. The reaction was diluted with ethyl acetate and washed withwater and brine. The residue was chromatographed to yield methyl2-ethoxy meta amino cinnamate as (E) and (Z) isomers (10 g, yield 75%).

Step (iii)

Methyl 2-ethoxy meta amino cinnamate (10 g, 1 eq, 42.5 mmol) obtained instep (ii) was treated with magnesium (20.4 g, 20 eq, 850 mmol) and drymethanol (500 ml). The reaction mixture was refluxed for 2-3 h, andallowed to stir at room temperature for 16 h. The reaction mixture wasdiluted with ethyl acetate and quenched with cold aqueous ammoniumchloride. The organic layer was washed with water and brine. The residuewas chromatographed using ethyl acetate and hexane to afford the titlecompound as viscous liquid (8.06 g, yield 80%).

¹H NMR (200 MHz, CDCl₃) δ: 1.15 (t, J=6.8 Hz, 3H), 2.96 (d, J=6.9 Hz,2H), 3.22-3.42 (m, 1H), 3.42- 3.65 (m, 2H), 3.70 (s, 3H), 4.01 (t, J=6.4Hz, 1H) 6.50-6.62 (aromatics, 3H), 7.06 (t, J=7.8 Hz, 1H).

IR (neat) cm⁻¹: 3360, 1738.

Mass m/z (CI): 224 (M+1).

Preparation 103-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide

Step (i)

To a solution of 2-nitro-5-fluorophenol (5 g, 1 eq, 31.6 mmol) and ethyl2-bromoacetate (3.8 ml, 1.1 eq, 34.8 mmol) in dry acetone (160 ml) wasadded anhydrous potassium carbonate (8.7 g, 2 eq, 63.2 mmol) and stirredat RT for 16 h. The reaction mixture was filtered through celite andthen condensed on rotavapour. The residue, was diluted with ethylacetate and washed with water and brine to yield crude compound (6 g,yield 78%), which was used in step (ii).

Step (ii)

The crude compound obtained in step (i) (6 g, 1 eq, 28.8 mmol) was takenin dry methanol (150 ml). To this iron powder (8.06 g, 5 eq, 144 mmol)and glacial acetic acid (25 ml, 15 eq, 432 mmol) was added and heated at110° C. for 4 h. The solvents were removed from the reaction mixture anddiluted with ethyl acetate. The ethyl acetate layer was washed withaqueous ammonium chloride, water and brine. The residue waschromatographed to yield3-oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine as solid (2.2 g, mp:204-206° C., yield 46%).

¹H NMR (200 MHz, CDCl₃+DMSO-d₆) δ: 4.52 (s, 2H), 6.60-6.70 (m, 2H), 6.88(dd, J=8.3 and 5.8 Hz, 1H), 10.63 (bs, 1H).

IR (KBr) cm⁻¹: 1677, 1622.

Mass m/z (CI): 168 (M+1).

Step (iii)

3-Oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (2.2 g, 1 eq, 13.1mmol) obtained in step (ii) in dry THF (10 ml) was added drop wise to arefluxing THF (60 ml) containing LAH (1.5 g, 3 eq, 39.5 mmol). It wasfurther refluxed for 3 h and quenched with ethyl acetate. To this water(1.5 ml), 15% sodium hydroxide (1.5 ml) and water (4.5 ml) were addedsequentially. Once Al(OH)₃.H₂O precipitated out, it was filtered thoughcelite. The filtrate was condensed on rotavapour and chromatographed(ethyl acetate and hexane) to yield7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, yield 65%) asyellow oil.

¹H NMR (200 MHz, CDCl₃) δ: 2.80 (bs, 1H), 3.38 (t, J=4.4 Hz, 2H), 4.24(t, J=4.4 Hz, 2H), 6.48-6.56 (aromatics, 3H).

IR (neat) cm⁻¹: 3395 (br), 2957, 1606.

Mass m/z (CI): 154 (M+1).

Step (iv)

A mixture of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, 1 eq,8.49 mmol) obtained in step (iii) above, 1,3-dibromo propane (8.6 ml, 10eq, 84.9 mmol) and anhydrous sodium carbonate (2.7 g, 3 eq, 25.4 mmol)in dry DMF (85 ml) was heated at 70° C. for 16 h. The reaction wasdiluted with ethyl acetate and washed with water and brine. The residuewas chromatographed using ethyl acetate and hexane to afford the titlecompound (1.1 g, yield 47%) as viscous oil.

¹H NMR (200 MHz, CDCl₃) δ: 2.10-2.28 (m, 2H), 3.30 (t, J=4 Hz, 2H), 3.38(t, J=6.7 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 4.24 (t, J=4.4 Hz, 2H),6.50-6.70 (aromatics, 3H).

Mass m/z (CI): 274 [M(⁷⁹Br)+1], 276 [M (⁸¹Br)+1].

Preparation 11 N-{(3,4-Dihydro-2H-benzo[b]oxazin-4-yl)propyl}benzylamine

Cesium hydroxide monohydrate (288 mg, 1.1 eq, 1.72 mmol), and grindedmolecular sieves 4A (500 mg) was stirred at RT in dry DMF (7 ml) for 15min. To this benzylamine (510 μl, 3 eq, 4.68 mmol), was added, followedby stirring for another 30 min. Finally3-(3,4-dihydro-2H-benzo[b][1,4]oxazine-4-yl)propyl bromide (400 mg, 1eq, 1.50 mmol) obtained in preparation 2, in DMF (3 ml) was added. Afterstirring for 16 h at RT, the reaction mixture was diluted with ethylacetate and washed with water and brine. The organic layer was condensedand chromatographed using chloroform/methanol to obtain the titlecompound as viscous liquid (307 mg, yield 70%).

¹H NMR (200 MHz, CDCl₃) δ: 1.77 (q, J=6.8 Hz, 2H), 2.00 (bs, 1H), 2.67(t, J=7.3 Hz, 2H), 3.20-3.28 (m, 4H), 3.76 (s, 2H), 4.16 (t, J=4.4 Hz,2H), 6.50-6.82 (aromatics, 4H), 7.18-7.38 (aromatics, 5H).

IR (neat) cm⁻¹: 3311 (br), 2931, 1669.

Mass m/z (CI): 283 (M+1).

Preparation 12 Methyl2-ethoxy-3-{4-(4-hydroxybenzyl)aminophenyl}propanoate

Methyl 2-ethoxy-3-(4-aminophenyl)propanoate (500 mg, 1 eq, 2.24 mmol)obtained in preparation 7, 4-hydroxybenzaldehyde (273 mg, 1 eq, 2.24mmol), and catalytic amount of p-TsOH were taken in DCM (5 ml) alongwith few pieces of molecular sieves (4A). The reaction mixture wasstirred at RT for 24 h, diluted with excess amount of ethyl acetate andwashed with aqueous sodium bicarbonate. The EtOAc layer was dried overanhydrous sodium sulfate and then condensed on rotary evaporator. Thecrude was dissolved in methanol (10 ml) and treated with Na(CN)BH₃ (166mg, 1.2 eq, 2.64 mmol) in presence of conc. HCl (220 mL) at, 0° C. andstirred for 2 h. The reaction mixture was diluted with excess amount ofethyl acetate, washed with water and brine. The EtOAc layer was driedover anhydrous sodium sulfate and then condensed on rotary evaporator.The residue was chromatographed using EtOAc/hexane to obtain the titlecompound as solid mass (405 mg, yield 55%, mp: 109-110° C.).

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=6.9 Hz, 3H), 2.89 (d, J=6.4 Hz,2H), 3.22-3.42 (m, 1H), 3.50-3.65 (m, 1H), 3.70 (bs, 5H, CO₂Me, —OH,—NH—), 3.98 (t, J=6.8 Hz, 1H), 4.20 (s, 2H), 6.56 (d, J=8.3 Hz, 2H),6.78 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H).

IR (KBr) cm⁻¹: 3369, 1680.

Mass m/z (CI): 330 [M+1].

Preparation 13 Methyl2-ethoxy-3-{3-(4-hydroxybenzyl)aminophenyl}propanoate

Methyl 2ethoxy-3-(3-aminophenyl)propanoate (1.0 mg, 1 eq., 4.4 mmol),obtained in preparation 9, 4-hydroxybenzaldehyde (547 mg, 1 eq,4.4mmol), and cat. amount of p-TsOH was taken in CH₂Cl₂ (25 ml) alongwith few pieces of activated molecular sieves (4A). The reaction wasmixture was stirred at RT for 24 h, which was then diluted with excessof ethyl acetate and washed with aqueous sodium bicarbonate. The EtOAclayer was dried over anhydrous sodium sulfate and then condensed onrotary evaporator. The crude was dissolved in MeOH (20 ml), and treatedwith Na(CN)BH₃ (415 mg, 1.5 eq, 6.6 mmol) in presence of conc. HCl (528mL) at 0° C. After 2 h of stirring, the reaction mixture was againdiluted with excess amount of ethyl acetate and washed with water andbrine. The EtOAc layer was dried over anhydrous sodium sulfate and thencondensed on rotary evaporator. The residue was chromatographed usingEtOAc/Hexanes to afford the title compound (450 mg, 30% yield) asviscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.19 (t, J=7.0 Hz, 3H), 1.29 (s, 1H, N—H),2.96 (d, J=6.3 Hz, 2H), 3.30-3.50 (m, 1H), 3.50-3.70 (m, 1H) 3.73 (bs,3H), 4.07 (t, J=6.6 Hz 1H), 4.21 (s, 2H), 6.50-6.70 (m, 3H), 6.81 (d,J=8.3 Hz, 2H) 7.11 (t, J=7.8, 1H), 7.22 (d, J=8.3 Hz, 2H) 7.39 (s, 1H,—OH).

IR (neat) cm⁻: 3391, 1738, 1607.

Mass m/z (CI): 330 [M+1].

Preparation 14 3-(3,4-Dihydro-2H-benzo[b][1,4]thiazin-4yl)propylbromide

A mixture of 3,4-dihydro-2H-benzo[b][1,4]thiazine (2.0 g, 1.0 eq, 13.24mmol), 1,3-dibromopropane (14 ml, 10 eq, 132.4 mmol) and anhydrousNa₂CO₃ (4.21 g, 3.0 eq, 39.7 mmol) in dry DMF (130 ml) was heated at 70°C. for 16 h. The reaction mixture was diluted with ethyl acetate (200ml) and washed with water and brine. The organic layer was dried(Na₂SO₄), condensed, and the residue was chromatographed using ethylacetate and hexanes to obtain the title compound as yellow oil (2.13 g,59% yield).

¹H NMR (200 MHz, CDCl₃) δ: 2.11-2.25 (m, 2H), 3.02 (t, J=4.4 Hz, 2H),3.20-3.28 (m, 4H), 3.62 (t, J=4.4 Hz, 2H), 6.60-6.72 (aromatics, 2H),6.90-7.20 (aromatics, 2H).

Mass m/z (CI): 271 [M (⁷⁹Br), 272 [M (⁷⁹Br)+1], 273 [M (⁸¹Br)], 271 [M(⁸¹Br)+1].

Preparation 15 2-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylbromide

A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (1.5 g, 1.0 eq, 11.12mmol), 1,3-dibromoethane (10 ml, 10 eq, 111.2 mmol) and anhydrous K₂CO₃(4.6 g, 3.0 eq, 33.36 mmol) in dry DMF (110 ml) was heated at 70° C. for16 h. The reaction mixture was diluted with ethyl acetate (200 ml),washed with water and brine. The organic layer was dried (Na₂SO₄),condensed, and the residue was chromatographed using ethyl acetate andhexane to obtain the title compound as yellow oil (940 g, 34%).

¹H NMR (200 MHz, CDCl₃) δ: 3.45 (t, J=4.4 Hz, 2H), 3.50-3.72 (m, 4H),4.24 (t, J=4.4 Hz, 2H), 6.65 (t, J=7.8 Hz, 2H), 6.78- 6.90 (aromatics,2H).

Mass m/z (CI): 241 [M (⁷⁹Br)], 242 [M (⁷⁹Br)+1], 243 [M (⁸¹Br)], 244 [M(⁸¹Br)+1].

Preparation 164-{2-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}aniline

Step (i)

A mixture of 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl bromide(500 mg, 1.0 eq, 2.07 mmol) obtained it preparation 15, 4-nitrophenol(288 mg, 1 eq, 2.07 mmol) and anhydrous K₂CO₃ (857 mg, 3.0 eq, 6.21mmol) in dry acetone (12 ml) was stirred at RT for 16 h. The reactionmixture was diluted with ethyl acetate (200 ml), washed with water andbrine. The organic layer was dried (Na₂SO₄), condensed. The crude masswas used for the step (ii).

Step (ii)

A methanolic solution (10 ml) of the crude product (600 mg, 1 eq, 2.0mmol), obtained in step (i) was hydrogenated at RT under atmosphericpressure using ammonium formate (2.6 g, 20 eq., 40 mmol) and 10% Pd/C ascatalyst (500 mg). After 6 h of stirring TLC indicated absence ofstarting material. The reaction mixture was filtered through celite andcondensed. The residue was chromatographed using ethyl acetate andhexane to obtain the title compound as viscous liquid (355 mg, 66%).

¹H NMR (200 MHz, CDCl₃) δ: 3.40 (bs, —NH₂), 3.51 (t, J=4.4 Hz, 2H), 3.65(t, J=5.8 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 4.23 (t, J=4.4 Hz, 2H),6.50-6.90 (aromatics, 4H).

Mass m/z (CI): 270 [M], 271 [M+1].

Preparation 173(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide

Step (i)

To a solution of 2-nitro-5-fluorophenol (1.0 g, 1 eq, 6.36 mmol) andethyl 2-bromopropionate (0.91 ml, 1.1 eq, 6.99 mmol) in dry acetone (32ml) was added anhydrous potassium carbonate (2.63 g, 3 eq, 19.08 mmol)and the reaction mixture was refluxed for 16 h. The reaction mixture wasfiltered through celite and then condensed on rotavapour. The residuewas diluted with ethyl acetate and washed with water and brine to yieldethyl 2-(2-nitro-5-fluorophenoxy)propanoate as crude compound (1.6 g,yield 98%), which was used in step (ii).

Step (ii)

The crude compound obtained in step (i) (1.6 g, 1 eq, 6.22 mmol) wastaken in dry methanol (150 ml). To this iron powder (5.23 g, 15 eq,93.37 mmol) and glacial acetic acid (5.6 ml, 15 eq, 93.37 mmol) wasadded and heated at 110° C. for 4 h. The solvents were removed from thereaction mixture and diluted with ethyl acetate. The ethyl acetate layerwas washed with aqueous ammonium chloride, water and brine. The residuewas chromatographed to yield2-methyl-3-oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine as solid(1.0 g, yield 88%).

Mp: 166-168° C.

¹H NMR (200 MHz, CDCl₃) δ: 1.59 (d, J=6.9 Hz, 3H); 4.67 (q, J=6.9 Hz,1H), 6.60-6.80 (aromatics, 3H), 8.61 (bs, 1H).

IR (KBr) cm⁻¹: 1677, 1610.

Mass m/z (CI): 182 (M+1).

Step (iii)

2-Methyl-3-oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.8 g, 1eq, 26.5 mmol) obtained in step (ii) in dry THF (60 ml) was added dropwise to a refluxing THF (200 ml) containing LAH (6.05 g, 6 eq, 159.1mmol). It was further refluxed for 3 h and quenched with ethyl acetate,and hydrolyzed with saturated aq. sodium sulfate. Once Al(OH)₃.H₂Oprecipitated out, it was filtered through celite. The filtrate wascondensed on rotavapour and chromatographed (ethyl acetate and hexane)to yield 2-methyl-7-fluoro-3,4-dihydro-2H-[b][1,4]oxazine (4.3 g, yield97%) as yellow oil. The crude product was used fir the next reaction.

¹H NMR (200 MHz, CDCl₃) δ: 1.36 (d, J=6.5 Hz, 3H); 3.05 (dd, J=11.3, 8.0Hz, 1H); 3.32 (d, J=11.8 Hz, 1H); 3.60 (bs, 1H, N—H); 4.18-4.30 (m, 1H),6.40-6.60 (aromatics, 3H).

IR (KBr) cm⁻¹: 3387, 2977, 2933, 1605, 1510.

Mass m/z (CI): 168 (M+1).

Step (iv)

A mixture of 2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b]1,4]oxazine (4.3g, 1 eq, 25.74 mmol) obtained in step (iii) above, 1,3-dibromo propane(26.1 ml, 10 eq, 257 mmol) and anhydrous sodium carbonate (8.2 g, 3 eq,77.2 mmol) in dry DMF (260 ml) was heated at 70° C. for 16 h. Thereaction mixture was diluted with ethyl acetate and washed with waterand brine. The residue was chromatographed using ethyl acetate andhexane to afford the title compound (3.5 g, yield 48%) as viscous oil.

¹H NMR (200 MHz, CDCl₃) δ: 1.35 (d, J=6.7 Hz, 3); 2.02-2.22 (m, 2H; 3.01(dd, J=11.3, 8.3 Hz, 1H); 3.32 (dd, J=11.6, 2.3 Hz, 1H); 3.22-3.58 (m,4H); 4.18-4.35 (m, 1H), 6.42-6.62 (aromatics, 3H).

Mass m/z (CI): 288 [M(⁷⁹Br)+1], 290 [M(⁸¹Br)+1].

Preparation 183-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-yl)propylbromide

Step (i)

Starting from 2-nitrophenol (10 g, 1 eq, 71.9 mmol) and ethyl2-bromopropionate (10.2 ml, 1.1 eq, 79.09 mmol) the procedure of Step(i), preparation 17 was followed to obtain ethyl2-(2-nitrophenoxy)propanoate in crude form (16 g) which was used forstep (ii).

Step (ii)

The crude compound obtained in step (i) (16 g, 1 eq, 62.2 mmol) wasconverted to 2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine as solid(10.0 g, yield 98%) following the procedure of step (ii), preparation17.

Mp: 164-166° C.

¹H NMR (200 MHz, CDCl₃) δ: 1.59 (d, J=6.7 Hz, 3H); 4.67 (q, J=6.7 Hz,1H), 6.80-7.00 (aromatics, 4H), 9.45 (bs, 1H).

IR (KBr) cm⁻¹: 3500, 3198, 2917, 1675, 1608, 1501.

Mass m/z (CI): 164 (M+1).

Step (iii)

2-Methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.0 g, 1 eq, 30.6mmol) obtained in step (ii) was reduced to2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.3 g, yield 90%) asyellow oil following the procedure of step (iii), preparation 17.

¹H NMR (200 MHz, CDCl₃) δ: 1.37 (d, J=6.1 Hz, 3H); 3.10 (dd, J=11.3, 8.1Hz, 1H); 3.34 (d, J=11.6, 2.5 Hz, 1H); 3.60 (bs, 1H, N—H); 4.18-4.30 (m,1H), 6.50-6.80 (aromatics, 4H).

IR (KBr) cm⁻¹: 3389, 2977, 2976, 1608, 1503.

Mass m/z (CI): 150 (M+1).

Step (iv)

From 2-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.5 g, 1 eq, 30.2mmol) obtained in step (iii) above, and 1,3-dibromo propane (30 ml, 10eq, 300 mmol) and following the procedure of step (iv), preparation 17title compound (3.5 g, yield 48%) was obtained as viscous oil.

¹H NMR (200 MHz, CDCl₃) δ: 1.29 (d, J=6.4 Hz, 3H); 2.05-2.25 (m, 2H);3.07 (dd, J=11.3, 8.3 Hz, 1H); 3.24 (dd, J=11.6, 2.3 Hz, 1H); 3.30-3.58(m, 4H); 4.18-4.35 (m, 1H), 6.50- 6.82 (aromatics, 4H).

Mass m/z (CI): 270 [M(⁷⁹Br)+1], 272 [M(⁸¹Br)+1].

Preparation 193-(2propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide

Step (i)

Starting from 2-nitrophenol (1.0 g, 1 eq, 7.19 mmol) and ethyl2-bromopentanoate (2.97 ml, 3.0 eq, 21.54 mmol) the procedure of step(i), preparation 17 was followed to obtain ethyl2-(2-nitrophenoxy)pentanoate (2.0 g) as crude which was used for step(ii).

Step (ii)

The crude compound obtained in step (i) (1.7 g, 1 eq; 6.36 mmol) wasconverted to 2-propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine as solid(1.2 g, yield 87% over 2 steps) following the procedure of step (ii),preparation 17.

Mp: 172-174° C.

¹H NMR (200 MHz, CDCl₃) δ: 0.98 (d, J=7.0 Hz, 3H); 1.40-1.70 (m, 2H);1.70-1.98 (m, 2H); 4.59 (t, J=6.4 Hz, 1H); 6.84-7.60 (aromatics, 4H),9.00 (bs, 1H).

IR (KBr) cm⁻¹: 3198, 2917, 1677, 1611, 1502.

Mass m/z (CI): 192 (M+1).

Step (iii)

2-Propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine (2.0 g, 1 eq, 10.4mmol) obtained in step (ii) was reduced to2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.65 g, yield 90%) ascrude following the procedure of step (iii), preparation 17 and procededfor the next reaction.

Mass m/z (CI): 178 (M+1).

Step (iv)

From 2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.65 g, 1 eq, 9.3mmol) obtained in step (iii) above, and 1,3-dibromo propane (9.4 ml, 10eq, 93 mmol) and following the procedure of step (iv), preparation 17title compound (915 mg, yield 33%) was obtained as viscous oil.

¹H NMR (200 MHz, CDCl₃) δ: 0.97 (t, J=7.0 Hz, 3H); 1.40-1.80 (m, 4H);2.00-2.25 (m, 2H); 3.10 (dd, J=11.6, 8.0 Hz, 1H); 3.27 (dd, J=11.6, 2.4Hz, 1H); 3.35-3.58 (m, 4H); 4.00-4.18 (m, 1H), 6.50- 6.90 (aromatics,4H).

Mass m/z (CI): 298 [M(⁷⁹Br)+1], 300 [M(⁸¹Br)+1].

Preparation 20 (S)-Ethyl 2-ethoxy-3-(4-aminophenyl)propionate

Step (i)

To a solution of (S)-(4-nitrophenyl) alanine (10 g, 47.6 mmol) in amixture of water (50 mL), H₂SO₄ (1M, 60 mL) and acetone (150 mL) at −5°C., was added under stirring, a solution of sodium nitrite (9.85 g,142.8 mmol) in water (40 mL) drop wise over a period of 30 min. Thereaction mixture was stirred at −5 to 0° C. for another 1.5 h, followedby stirring at room temperature for 16 h. Acetone was removed and thenthe reaction mixture was diluted with 500 mL ethyl acetate. Organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated. The crude mass was purified by crystallization fromisopropyl acetate (9.0 g, 96%).

Mp: 134-136° C.

[α]_(D): −25° (c 1.0, MeOH)

¹H NMR (CDCl₃) δ: 3.04 (dd, J=14, 7.8 Hz, 1H), 3.24 (dd, J=14, 4, Hz,1H), 4.39 (dd, J =7.3, 4.1 Hz, 1H), 7.42 (d, J =8.7 Hz,2H), 8.16 (d,J=8.7 Hz, 2H).

IR (neat) cm⁻¹: 3485, 3180, 2927, 1715, 1515, 1343.

Mass m/z (CI): 212 (M+1).

Step (ii)

(S)-2-Hydroxy-3-(4-nitrophenyl)propionic acid (9.0 g, 42.6 mmol)obtained from step (i) above, was dissolved in dry EtOH (300 mL). Tothis solution was added conc. H₂SO₄ (326 mL, 5.9 mmol), and refluxed for5 to 6 h. The reaction mixture was neutralized with aqueous sodiumbicarbonate. Ethanol was condensed on rotavapor, and the residue wasdissolved on ethyl acetate. Organic layer was washed with aqueous sodiumbicarbonate, water, brine, and then dried over anhydrous Na₂SO₄, andconcentrated. Desired product was obtained from the crude mass bycrystallizing from diisopropylether (8.0 g, 78.5 %).

Mp: 74-76° C.

[α]_(D): −13° (c 1.0, MeOH)

¹H NMR (CDCl₃) δ: 1.30 (t, J=7 Hz 3H, 3.06 (dd, J=14, 7, Hz, 1H), 3.25(dd, J=14, 4.3, Hz, 1H), 4.25 (q, J=7 Hz, 2H), 4.25 (dd, J=7, 4.3 Hz,1H), 7.42 (d, J=8.7 Hz, 2H), 8.16 (d, J=8.7 Hz, 2H).

IR (neat) cm⁻¹: 3432, 2924, 1736, 1518, 13471.

Mass m/z (CI): 240 (M+1).

Step (iii)

To a mixture of (S)-Ethyl 2-Hydroxy-3-(4-nitrophenyl)propionate (4.77 g,19.95 mmol), obtained in step ii above, molecular sieves (4 A) (5.0 g)and powdered Ag₂O (13.8 g, 59.8 mmol) in dry acetonitrile (100 mL), wasadded ethyl iodide (6.4 mL, 79.8 mmol) at room temperature. The reactionmixture was heated at 60° C. for 16 h. The reaction mixture was filteredthrough celite, and concentrated. The crude mass was chromatographedusing ethyl acetate and hexanes to obtain the desired product as viscousliquid (3.5 g, 67% isolated yield). Unreacted starting material wasrecovered (900 mg which could be reused.

[′]_(D): −26° (c 1.0, MeOH)

¹H NMR (CDCl₃) δ: 1.15 (t, J=7 Hz, 3H) 1.26 (t, J=7.Hz, 3H); 3.10 (d,J=3.8 Hz 1H); 3.13 (s, 1H); 3.16-3.35 (m, 1H); 3.45-3.65 (m, 1H); 4.03(dd, J=7,5, 5.4 Hz, 1H); 4.21 (q, J=7.2 Hz, 2H); 7.43 (d, J=8.6 Hz, 2H);8.15 (d, J=8.6 Hz, 2H).

IR (neat) cm⁻¹: 2980, 1747, 1604, 1521, 1347.

Mass m/z (CI): 268 (M+1).

Step (iv)

(S)-Ethyl 2-ethoxy-3-(4-nitrophenyl)propionate (6.0, 25.3 mmol),obtained in step (iii) above, was dissolved in dry methanol (100 mL). Tothis solution was added 10% Pd/C (2.0 g), and was hydrogenated usinghydrogen gas (20 psi) for 3-4 h. The reaction mixture was filteredthrough celite, and the filtrate was concentrated to provide a syrupymass. The product was obtained in quantitative yield.

[α]_(D): −14.2° (c 1.0, MeOH).

Chiral HPLC: >98% ee.

¹H NMR (CDCl₃) δ: 1.16 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H), 2.90(d, J=6.3 Hz, 2H), 3.30 (bs, 2H, NH₂), 3.24-3.42(m, 1H), 3.50-3.70 (m,1H), 3.94 (t, J=6.3 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 6.62 (d, J=8.3 Hz,2H), 7.03 (d, J=8.0 Hz, 2H).

IR (neat) cm⁻¹: 3372, 1738.

Mass m/z (CI): 238 (M+1), 192 (M-OC₂H₅).

Preparation 21

(S)-Ethyl 2-methoxy-3-(4-aminophenyl)propionate

Step (i)

To a mixture of (S)-Ethyl 2-Hydroxy-3-(4-nitrophenyl)propionate (12.5 g,52.3 mmol), obtained in step (ii) of preparation 20, and powdered Ag₂O(36.3 g, 157 mmol) in dry acetonitrile (260 mL) was added methyl iodide(13 mL, 209.2 mmol) at room temperature. Activated molecular sieves (4A) (12.5 g) were added and then the reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was filtered through celite,and concentrated. The crude mass was chromatographed using ethyl acetateand hexanes to obtain the desired product as viscous liquid (10.0 g,75%).

[α]_(D): −30.10° (c 1.0, MeOH)

¹H NMR (CDCl₃) δ: 1.24 (t, J=7.1 Hz 3H); 3.09 (d, J=5.4 Hz, 1H); 3.12(d, J=2.7 Hz, 1H); 3.35 (s, 3H); 396 (dd, J=7.5, 5.1 Hz, 1H) 4.19 (q, J=7.1 Hz, 2H); 7.39 (d, J=8.6 Hz, 2H); 8.13 (d, J=8.6 Hz, 2H).

IR (neat) cm⁻¹: 2995, 1747, 1604, 1521, 1343.

Mass m/z (CI): 254 (M+1).

Step (ii)

(S)-Ethyl 2-methoxy-3-(4-nitrophenyl)propionate (8.0, 31.6 mol) obtainedin step (i) above, was dissolved in dry methanol (200 mL). To thissolution was added 10% Pd/C (2.5 g), and hydrogenated using hydrogen gas(20 psi) for 3-4 h. The reaction mixture was filtered through celite,and concentrated to a syrupy mass. After column chromatography usingethyl acetate/hexanes the desired product was isolated as thick liquid(7.0 g, quantitative).

[α]_(D): −14.1° (c 1.0, MeOH).

Chiral HPLC: >98% ee.

¹H NMR (CDCl₃) δ: 1.23 (t, J=7.2 Hz, 3H), 2.91 (d, J=6.1 Hz, 2H), 3.30(bs, 2H, NH₂), 3.34 (s, 3H), 3.88 (t, J 6.2 Hz, 1H), 4.17 (q, J=7.2 Hz,2H), 6.62 (d, J=8.3 Hz, 2H), 7.01 (d, J=8.1 Hz, 2H).

IR (neat) cm⁻¹: 3372, 2985, 2932, 1739, 1627, 1519.

Mass m/z (CI): 223 (M), 234 (M+1), 192 (M-OMe).

Preparation 22 Ethyl 2-isopropoxy-3-(4-aminophenyl)propionate

Step (i):

4-nitrophenylalanine (5 g, 1 eq, mmol) was added in portions to asolution of dry ethanol (mL) and thionylchloride (mL) at −5° C. It wasstirred at that temperature for another one hour, followed by stirringat RT for 16 h. The reaction mixture was condensed on rotavapour,azeotroped with toluene, and then dried over high vaccum pump to obtain4-nitrophenylalanine ethyl ester hydrochloride as white solid(quantitative yield).

Step (ii):

4-nitrophenylalanine ethyl ester hydrochloride (2 g, 1.0 eq, 7.28 mmol)obtained in step(i) was dissolved in ethyl acetate (150 mL). To thatNa₂CO₃ (386 mg, 0.5 eq, 3.64 mmol) was added and was stirred for 15 min.The reaction mixture was washed with aq. NaHCO₃. The organic layer wasdried (Na₂SO₄), and condensed to obtain 4-nitrophenylalanine ethyl esteras thick oil (1.55 g, 89%).

Step (iii):

4-nitrophenylalanine ethyl ester (1.55 g, 1.0 eq, 6.51 mmol), obtainedin step(ii) above was dissolved in chloroform (33 mL). To that glacialacetic acid (20 μL, 0.05 eq, 0.33 mmol), and isoamylnitrite (958 μL, 1.1eq, 7.16 mmol) were added and the reaction mixture was heated at refluxfor 30 min. The reaction mixture was diluted with chloroform, and waswashed with aq. NaHCO₃. The organic layer was dried (Na₂SO₄) andcondensed (caution!) to a yellowish liquid.

Step (iv):

The liquid (1.54 g, 1.0 eq, 6.18 mmol) thus obtained in step (iii), wasdissolved in dry isopropanol (31 mL), and to that catalytic amount ofRh₂(OAc)₄.2H₂O (38 mg, 0.02 eq, 0.12 mmol) was added and the reactionmixture was stirred at room temperature for 16 h. Isopropanol wascondensed, and the reaction mixture was diluted with ethyl acetate. Theorganic layer was washed with water and brine, dried (Na₂SO₄), andconcentrated. Column chromatography, using ethyl acetate and hexanes,provided the desired compound ethyl2-isopropoxy-3-(4-nitrophenyl)propionate (1.25 g, 61% overall).

¹H NMR (200 MHz, CDCl₃) δ: 0.92 (d, J=5.8 Hz, 3H, 1.16 (d, J=5.8 Hz,3H), 1.27 (t, J=7.4 Hz, 3H), 3.00-3.10 (m, 2H), 3.52 (quintet, 1H); 4.08(dd, J=8.7 and 4.8 Hz, 1H), 4.21 (q, J=7.4 Hz, 2H), 7.43 (d, J=8.7 Hz,2H), 8.16 (d, J=8.7 Hz, 2H).

IR (neat) cm⁻¹: 2975, 1747, 1602, 1522, 1347.

Mass m/Z (CI): 282 [M+1]

Step (v):

Ethyl 2-isopropoxy-3-(4-nitropohenyl)propionate (1.52 g, 5.4 mmol)obtained in step (v) was hydrogenated under 10 psi pressure of molecularhydrogen using 10% Pd/C (700 mg) as catalyst in ethyl acetate (200 mL)at room temperature for 3-4 h. The desired product was isolated afterfiltering the reaction mixture and concentrating the filterate underreduced pressure. Column chromatography of the crude mass using ethylacetate acid hexanes provided the desired compound ethyl2-isopropoxy-3-(4-aminophenyl)propionate (1.16 g, 86% overall).

¹H NMR (200 MHz, CDCl₃) δ: 0.97 (d, J 32 5.8 Hz, 3H), 1.15 (d, J=5.8 Hz,3H), 1.23 (t, J=7.0 Hz, 3H), 2.80-2.95 (m, 2H), 3.49 (quintet, 1H); 3.98(dd, J=8.1 and 5.7 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 6.61 (d, J=8.3 Hz,2H), 7.03 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3455, 3371, 2975, 2929, 1737, 1626, 1519.

Mass m/z (CI): 252 [M+1]

EXAMPLE 1 Ethyl3-[4-{3-(3,4-dihydro-2H-benzo[b]1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (2 g, 1 eq, 8.4 mmol)obtained in preparation1,3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (2.36 g, 1.1eq, 9.3 mmol), obtained in preparation 2, and anhydrous K₂CO₃ (3.5 g, 3eq, 25 mmol), were heated at 70° C. in DMF (40 ml) for 24 h. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine. The residue was chromatographed using a mixture of ethyl acetateand hexane as eluent to afford the title compound as a viscous liquid(1.04 g, yield 30%).

¹H NMR (200 MHz, CDCl₃) 1.17 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H),1.92 (q, J=7.0 Hz, 2H), 2.90 (d, J=6.8 Hz, 2H), 3.20 (t, J=7.0 Hz, 2H),3.22-3.41 (m, 5H), 3.45-3.62 (m, 1H), 3.95 (t, J=6.4 Hz, 1H), 4.05-4.37(m, 4H), 6.65 (d, J=8.3 Hz, 2H), 6.61-6.85 (m, 4H), 7.05 (d, J=8.3 Hz,2H).

IR (neat) cm⁻¹: 3396 (br), 1740.

Mass m/z (CI): 413 (M+1).

EXAMPLE 23-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid

Ethyl3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate(700 mg, 0.98 mmol) obtained in example 1, was hydrolyzed using lithiumhydroxide monohydrate (123 mg, 2.9 mmol), in methanol-water at RT tillall the starting material was consumed (4 to 5 h). The reaction mixturewas diluted with water, acidified with dil. HCl to adjust the pH to ˜4-5and then extracted with ethyl acetate. The ethyl acetate layer was driedover Na₂SO₄ and concentrated on rotavapour. The residue waschromatographed using methanol and chloroform to yield the titlecompound as viscous liquid (256 mg, yield 68%).

¹H NMR (200 MHz, CDCl₃) δ: 1.19 (t, J=7.4 Hz, 3H), 1.94 (q, J=7.4 Hz,2H), 2.90 (dd, J=14.0 and 7.0 Hz, 1H), 3.05 (dd, J=14.0 and 4.9 Hz, 1H),3.21 (t, J=6.8 Hz, 2H), 3.25-3.40 (m, 5H), 3.40-3.62 (m, 1H), 4.00-4.17(m, 1H), 4.18-4.22 (m, 2H), 6.59 (d, J=8.3 Hz, 2H), 6.65-6.85 (m, 4H),7.06 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3500, 1725.

Mass m/z (CI): 385 (M+1)

EXAMPLE 33-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid arginine sale

To a solution of3-[4-{3-(3,4-dihydro2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid (200 mg, 1 eq, 0.52 mmol) obtained in example 2, in drymethanol:dichloroethane (10:1) (5 ml), L-arginine (90.5 mg, 1 eq, 0.52mmol) was added and allowed to stir for 3-4 h. The solvent was reducedon rotavapour followed by benzene azeotrope. The residue was dried underhigh vacuum pump to yield the title compound as a free flowing solid(yield 100%), mp: 92-94° C.

DSC: endotherm (weak and broad): 66.6° C.

XRD: Amorphous.

EXAMPLE 4 Ethyl3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate

3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.85 mg, 1.24 mmol), ethyl2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate (500mg, 1 eq, 1.13 mmol) obtained in preparation 3, and anhydrous K₂CO₃ (468mg, 3 eq, 3.39 mmol), were heated at 70° C. in DMF (6 ml) for 16 h. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine. The residue was chromatographed using a mixture of ethyl acetateand hexanes as diluent to afford the title compound as thick liquid (363mg, yield 63%).

¹H NMR (200 MHz, CDCl₃) δ: 0.88 (bt, J=6.3 Hz, 3H), 1.05-1.42 (m, 14H),1.42-1.68 (m, 2H), 2.92 (d, J=6.8 Hz, 2H), 3.25 (t, J=7.3 Hz, 2H),3.30-3.45 (m, 1H), 3.50-3.70 (m, 3H), 3.97 (t, J=6.6 Hz, 1H), 4.08 (t,J=7.3 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 6.57 (d, J=8.3 Hz,2H), 6.99 (s, 4H), 7.10 (d, J=8.0 Hz, 2H).

IR (neat) cm⁻¹: 1747.

Mass m/z (CI): 511 (M+1).

EXAMPLE 53-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoicacid

3-[4-N-Heptyl-N-{2-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate(350 mg, 1 eq, 0.68 mmol) obtained in example 4, was hydrolyzed usinglithium hydroxide monohydrate (86 mg, 3 eq, 2.04 mmol) in methanol waterat RT till all the starting material was consumed (4 to 5 h). Thereaction mixture was diluted with water, acidified with dil. HCl to pH2-3 and then extracted with ethyl acetate. The ethyl acetate layer wasdried over Na₂SO₄ and concentrated on rotavapour. The residue waschromatographed using methanol and chloroform to yield the titlecompound as a gummy mass (197 mg, yield 60%).

¹H NMR (200 MHz, CDCl₃) δ: 0.88 (bt, J=6.3 Hz, 3H), 1.05-1.42 (m, 11H),1.42-1.68 (m, 2H), 2.82-3.10 (m, 2H), 3.25 (t, J=7.3 Hz, 21), 3.40-3.70(m, 4H), 3.98-4.15 (m, 3H), 4.56 (s, 2H), 6.67 (d, J=8.3 Hz, 21), 6.98(s, 4H), 7.10 (d, J=8.0 Hz, 2H).

IR (neat) cm⁻¹: 3500 (br), 1687.

Mass m/z (CI): 483 (M+1).

EXAMPLE 63-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoicacid arginine salt

3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoicacid (150 mg, 1 eq, 0.31 mmol) obtained in example 5, and L-arginine (54mg 1 eq, 0.3 mmol ) were taken in dry method (2 ml), and stirred at RTfor 2-3 h. The solvent was removed on rotavapour followed by benzeneazeotrope. The residue was dried under high vacuum pump to yield thetitle compound as a free flowing solid (yield 100%), mp: 118-120° C.

EXAMPLE 7 Methyl2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate

2-(3,4-Dihydro-2H-benzo[b]oxazin-4-yl)carboxymethyl chloride (208 mg, 1eq, 0.98 mmol) obtained in preparation 4, and methyl2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate (300 mg, 1 eq, 0.89mmol) obtained in preparation 6, in acetonitrile (5 ml), was treatedwith anhydrous sodium carbonate (285 mg, 3 eq, 2.68 mmol). The reactionmixture was stirred at 80° C. for 4 h. TLC indicated absence of startingmaterials. The reaction mixture was diluted with ethyl acetate, washedwith water and brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated on rotary evaporator. The residue waschromatographed using ethyl acetate and hexane to afford the titlecompound (250 mg, yield 55%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 0.86 (bt, J=6.3 Hz, 3H), 1.14 (t, J=6.8 Hz,3H), 1.20-1.40 (m, 8H), 1.50-1.70 (m, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.99(d, J=6 Hz, 2H), 3.22-4.40 (m, 11H), 3.67 (s, 3H), 6.80-7.26 (aromatics,8H).

IR (neat) cm⁻¹: 1752, 1683.

Mass m/z (CI): 511 [M+1].

EXAMPLE 82-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoicacid

Methyl2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate(240 mg, 1 eq, 0.47 mmol) obtained in example 7, was hydrolyzed usinglithium hydroxide monohydrate (99 mg, 5 eq, 2.35 mmol) in methanol-waterat RT (takes 4-5 h). The reaction mixture was acidified with aqueous HCland the organic layer was extracted with ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate and concentratedon rotary evaporator. The residue was chromatographed (ethyl acetate andhexane→methanol/chloroform) to afford the title compound (130 mg, yield56%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 0.86 (bt, J=6.3 Hz, 3H), 1.10-1.40 (m, 11H),1.40-1.60 (m, 2H), 2.79 (t, J=7.5 Hz, 2H), 2.90-4.22 (m, 13H), 6.80-7.26(aromatics, 8H).

Mass m/z (CI): 497 [M+1].

EXAMPLE 92-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoicacid arginine salt

2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-2-oxoethyl)aminomethyl}phenyl]propanoicacid (90 mg, 0.18 mmol) obtained in example 8, and L-arginine (32 mg,0.18 mmol) were taken in dry methanol (2 ml), and stirred at RT for 2-3h. The solvent was removed oil rotavapour followed by benzene azeotrope.The residue was dried under high vacuum pump to yield the title compoundas a free flowing solid (yield 1000%), mp: 118-120° C.

EXAMPLE 10 Methyl3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate

A solution of methyl 2-ethoxy-3-(4-aminophenyl)propanoate (337 mg, 1 eq,1.51 mmol) obtained in preparation 7,5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentyl bromide (450 mg,1 eq, 1.51 mmol) obtained in preparation 8, in DMF (6 ml) was treatedwith anhydrous potassium carbonate (627 mg, 3 eq, 4.54 mmol) and thereaction mixture was stirred at 70° C. for 6 h. The reaction mixture wasdiluted with ethyl acetate, washed with water and brine. The organiclayer was dried over anhydrous sodium sulfate add concentrated on rotaryevaporator. The residue was chromatographed using ethyl acetate andhexane to afford the title compound as a viscous liquid (179 mg, yield27%).

¹H NMR (200 MHz, CDCl₃) δ: 1.16 (t, J7.0 Hz, 3H), 1.50-1.70 (m, 2H),1.70-1.90 (m, 2H), 2.64 (t, J=7.0 Hz, 2H), 2.89 (d, J=6.9 Hz, 2H), 3.08(t, J=6.7 Hz, 2H), 3.22-3.42 (m, 1H), 3.42-3.62 (m, 2H), 3.68 (s, 3H),3.88-4.00 (m, 3H), 4.26 (t, J=4.8, 2H), 6.50 (d, J=7.8 Hz, 2H,aromatics), 6.82-7.10 (aromatics, 4H), 7.04 (d, J=7.8 Hz, 2H,aromatics).

IR (KBr) cm⁻¹: 3408, 1739, 1683.

Mass m/z (CI): 441 [M+1].

EXAMPLE 113-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoicacid

Methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate(211 mg, 1 eq, 0.48 mmol) obtained in example 10, was hydrolyzed usinglithium hydroxide monohydrate (60 mg, 3 eq, 1.44 mmol) in methanol-waterat RT (takes 4-5 h). The reaction mixture was diluted with water,acidified (pH 3-4) with aqueous HCl and then extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous sodium sulfateand concentrated on rotary evaporator. The residue was chromatographed(ethyl acetate and hexane→methanol/chloroform) to afford the titlecompound (139 mg, yield 68%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.14 (t, J=7.0 Hz, 3H), 1.50-1.90 (m, 2H),2.62 (t, J=6.8 Hz, 2H), 2.80-3.15 (m, 4H), 3.22-3.42 (m, 1H), 3.42-3.62(m, 1H), 3.82-4.00 (m, 3H), 4.25 (t, J=4.9, 2H), 6.40-7.30 (br shoulder,N—H, CO₂H), 6.55 (d, J=7.8 Hz, 2H, aromatics), 6.82-7.10 (aromatics,4H), 7.04 (d, J=7.8 Hz, 2H, aromatics).

IR (KBr) cm⁻¹: 3408, 1719, 1680.

Mass m/z (CI): 427 [M+1].

EXAMPLE 123-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoicacid arginine salt

3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoicacid (120 mg, 1 eq, 0.28 mmol) obtained in example 11, and L-arginine(49 mg, 1 eq. 0.28 mmol) were taken in dry methanol (3 ml), and stirredat RT for 2-3 h. The solvent was removed on rotavapour followed bybenzene azeotrope. The residue was dried under high vacuum pump to yieldthe title compound as a free filing solid (yield 100%), mp: 137-139° C.

EXAMPLE 13 Methyl3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Methyl 2-ethoxy-3-(3-aminophenyl)propanoate (200 mg, 1 eq, 0.89 mmol)obtained in preparation 9,3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (253 mg, 1.1eq, 0.98 mmol) obtained in preparation 2, and anhydrous Na₂CO₃ (285 mg,3 eq, 2.68 mmol) were heated at 70° C. in DMF (5 ml), for 24 h. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine. The residue was chromatographed using ethyl acetate and hexane toafford the title compound (304 mg, yield 86%) as viscous liquid.

¹NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=7 Hz, 3H), 1.98 (q, J=7 Hz, 2H),2.92 (d, J=6.8 Hz, 2H), 3.19 (t, J=7 Hz, 2H), 3.22-3.41 (m, 5H),3.45-3.62 (m, 1H), 3.70 (s, 3H), 4.02 (t, J=6.4 Hz, 1H), 4.22 (t, J=4.3Hz, 2H), 6.40-6.82 (m, aromatics, 6H), 6.75 (d, J=7.8 Hz, 1H), 7.08 (t,J=7.8 Hz, 1H).

IR (neat) cm⁻¹: 3380 (br), 1743, 1680.

Mass m/z (CI): 399 (M+1).

EXAMPLE 143-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid

Methyl3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate(350 mg, 1 eq, 0.87 mmol) obtained in example 13, was hydrolyzed usinglithium hydroxide monohydrate (110 mg, 3 eq, 2.64 mmol), inmethanol-water at RT till all the starting material is consumed (4 to 5h). The reaction mixture was diluted with water, acidified (pH ˜4-5)with dil HCl and then extracted with ethyl acetate. The ethyl acetatelayer was dried over anhydrous sodium sulfate and concentrated on rotaryevaporator. The residue was chromatographed using methanol andchloroform to afford the title compound (203 mg, yield 61%) as viscousoil.

¹H NMR (200 MHz, CDCl₃) δ: 1.19 (t, J=7.4 Hz, 3H), 1.94 (q, J=7.4 Hz,2H), 2.85-3.60 (m, 10H), 4.00-4.17 (m, 1H), 4.23 (t, J=4.4 Hz, 2H), 4.95(bs, NH, CO₂H), 6.42-7.20 (aromatics, 8H).

IR (neat) cm⁻¹: 3500 (br), 1727.

Mass m/z (CI): 385 (M+1).

EXAMPLE 153-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid arginine salt

3-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid (90 mg, 1 eq, 0.23 mmol) obtained in example 14, and L-arginine(40.8 mg, 1 eq, 0.23 mmol) were taken in dry methanol (5 ml), andstirred at RT for 2-3 h. The solvent was removed on rotavapour followedby benzene azeotrope. The residue was dried under high vacuum pump toyield the title compound as a free flowing solid (yield 100%), mp:178-180° C.

EXAMPLE 16 Methyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Methyl 2-ethoxy-3-(4-aminophenyl)propanoate (405.8 mg, 1 eq, 1.82 mmol)obtained in preparation 7,3(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (500mg, 1 eq, 1.82 mmol) obtained in preparation 10, and anhydrous Na₂CO₃(572 mg, 3 eq, 5.4 mmol), were heated at 70° C. in acetonitrile for 24h. The reaction mixture was diluted with ethyl acetate, washed withwater and brine. The residue was chromatographed using ethyl acetate andhexane to afford the title compound (333 mg, yield 44%) a viscousliquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=7 Hz, 3H) 1.88 (q, J=7 Hz, 2H),2.91 (d, J=6.8 Hz, 2H), 3.10-3.42 (m, 1H), 3.69 (s, 3H), 3.98 (t, J=6.3Hz, 1H), 4.22 (t, J=3.9 Hz, 2H), 6.04-6.70 (m, aromatics, 5H), 7.04 (d,J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3382 (br), 1746, 1616.

Mass m/z (CI): 417 (M+1).

EXAMPLE 173-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid

Methyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate(180 mg, 1 eq, 0.43 mmol) obtained in example 16, was hydrolyzed usinglithium hydroxide monohydrate (55 mg, 3 eq, 1.2 mmol), in methanol-waterat RT till all the starting material is consumed (4 to 5 h). Thereaction mixture was diluted with water, acidified (pH ˜4-5) with dil.HCl and then extracted with ethyl acetate. The ethyl acetate layer wasdried over anhydrous sodium sulfate and concentrated on rotaryevaporator. The residue was chromatographed using ethyl acetate andhexanes→methanol and chloroform to afford the title compound (121 mg,yield 70%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.19 (t, J=7.4 Hz, 3H), 1.94 (quintet, J=7.4Hz, 2H), 2.85-3.10 (m, 2H), 3.10-3.20 (m, 6H), 3.40-3.70 (m, 2H),3.90-4.10 (m, 1H), 4.10-4.30 (m, 2H), 6.20 (bs, CO₂H), 6.42-6.70 (m,aromatics, 5H), 7.07 (d, J=8.3 Hz, 2H).

IR (KBr) cm⁻¹: 3394, 1725, 1619.

Mass m/z (CI): 403 (M−1).

EXAMPLE 18

3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid arginine salt

3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid (120 mg, 1 eq, 0.298 mmol) obtained in example 17, and L-arginine(52 mg, 1 eq, 0.298 mmol) were taken in dry methanol (2 ml), and stirredat RT for 2-3 h. The solvent was removed on rotavapour followed bybenzene azeotrope. The residue was dried under high vacuum pump to yieldthe title compound as a free flowing solid (yield 100%), mp: 158-160° C.

EXAMPLE 19 Methyl2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)proploxy)benzyl}aminophenyl]propanoate

A mixture of methyl2-ethoxy-3-{4-(4-hydroxybenzyl)aminophenyl}propanoate (600 mg, 1 eq,1.82 mmol) obtained in preparation 12,3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (467 mg, 1 eq,1.82 mmol) obtained in preparation 2, and anhydrous K₂CO₃ (755 mg, 3 eq,5.46 mmol) in DMF (10 ml) was stirred at RT for 16 h. The reaction wasdiluted with ethyl acetate, washed with water and brine. The organiclayer was dried over anhydrous sodium sulfate and was concentrated onrotary evaporator. The residue was chromatographed using EtOAc/hexanesto afford the title compound (520 mg, 56% yield) as thick liquid.

¹H NMR (CDCl₃, 200 MHz) δ: 1.19 (t, J=7.0 Hz, 3H), 2.00-2.20 (m, 2H),2.90 (d, J=6.3 Hz, 2H), 3.30-3.60 (m, 6H), 3.70 (bs, 3H), 3.8-4.10 (m,3H+NH), 4.10-4.25 (m, 4H), 6.57 (d, J=8.3 Hz, 2H), 6.60-6.90 (m, 6H),7.04 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H).

IR (neat) cm^(−‘): 3401 (br), 1742, 1614.

Mass m/z (CI): 504 [M], 505 [M+1].

EXAMPLE 20

Methyl2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate

The title compound was prepared (340 mg, yield 90%) as viscous liquidfrom a mixture of methyl2-ethoxy-3-{3-(4-hydroxybenzyl)aminophenyl}propanoate (250 mg, 1 eq,0.75 mmol) obtained in preparation 13, and3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (192 mg, 1 eq,0.75 mmol) obtained in preparation 2, by following the similar procedureas described for example 19.

¹H NMR (200 MHz, CDCl₃) δ: 1.19 (t, J=7.0 Hz, 3H), 1.95-2.18 (m, 2H),2.90 (d, J=6.3 Hz, 2H), 3.22-3.60 (m, 6H), 3.70 (bs, 3H), 3.90-4.10 (m,3H), 4.10-4.25 (m, 4H), 6.42-6.90 (aromatics, 8H), 7.05 (t, J=7.8, 1H),7.20-7.30 (m, aromatics, 3H).

IR (neat) cm⁻¹ : 3407 (br), 1742, 1607.

Mass m/z (CI): 504 [M], 505 [M+1].

EXAMPLE 212-Ethoxy-3-[4-}4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid

Methyl2-ethoxy-3-[4-{4-(3-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate(510 mg, 1 eq, 1.01 mmol) obtained in example 19, was hydrolyzed usinglithium hydroxide monohydrate (127 mg, 3 eq, 3.03 mmol) inmethanol-water at RT till all the starting material was consumed (4 to 5h). The reaction mixture was diluted with water, acidified (pH ˜3-4)with dil HCl and then extracted with EtOAc. The residue waschromatographed using ethyl acetate/hexanes to yield the title compoundas sticky liquid (250 mg, 51%).

¹H NMR (200 MHz, CDCl₃) δ: 1.18 (t, J=6.9 Hz, 3H), 1.26 (t, J=7.3 Hz,1H, N—H), 1.98-2.18 (m, 2H), 2.90 (dd, J=14.1, 7.4 Hz, 1H), 3.04 (dd,J=14.1, 4.4 Hz, 1H), 3.35 (t, J=4.2 Hz, 2H), 3.40-3.64 (m, 4H),3.95-4.10 (m, 3H); 4.10-4.25 (m, 4H), 6.57 (d, J=8.3 Hz, 2H), 6.60-6.82(m, 4H), 6.88 (d, J=8.3 Hz, 2H), 7.05 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3Hz, 2H).

IR (neat) cm⁻¹: 3407, 1723, 1610.

Mass m/z (CI): 490 [M], 491 [M+1].

EXAMPLE 222-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid

The title compound was prepared (220 mg, yield 53%) as viscous liquidfrom methyl 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate (420mg, 0.83 mmol) obtained in example 20, by following the similarprocedure as described for example 21.

¹H NMR (200 MHz, CDCl₃) δ: 1.15 (t, J=6.9 Hz, 3H), 1.26 (t, J=7.3 Hz,1H, N—H), 1.98-2.18 (m, 2H), 2.90 (dd, J=14.1, 7.8 H 1H), 3.05 (dd,J=13.7, 3.9 Hz, 1H), 3.30-3.60 (m, 6H), 3.70 (bs, 3H), 4.00-4.10 (m,3H), 4.10-4.25 (m, 4H), 6.42-6.90 (m, aromatics, 8H), 7.09 (t, J=7.8,1H), 7.20-7.30 (m, aromatics, 3H).

IR(neat) cm⁻¹: 3407 (br), 1725, 1606.

Mass m/z (CI): 491 [M+1].

EXAMPLE 232-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophehyl]propanoicacid arginine salt

2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid (250 mg, 1 eq, 0.5 mmol) obtained in example 21, and L-arginine(88.7 mg, 1 eq, 0.51 mmol) was stirred in dry methanol (3 ml) for 3-4 hat RT. The solvent was condensed on rotavapour, followed by benzeneazeotrope. The residue was dried under high vacuum pump to yield thetitle compound as a solid (yield 100%), mp: 141-142° C.

EXAMPLE 242-Ethoxy-3-[3-{4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid arginine salt

2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid (140 mg, 1 eq, 0.28 mmol) obtained in example 22, and L-arginine(50 mg, 1 eq, 0.28 mmol) was stirred in dry methanol (3 ml) for 3-4 h atRT. The solvent was condensed on rotavapour and followed by benzeneazeotrope. The residue was dried under high vacuum pump to yield thetitle compound as a solid (yield 100%), mp: 152-154° C.

EXAMPLE 25 Ethyl2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate

A mixture of 3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylbromide(1.76 g, 1.1 eq, 6.5 mmol), obtained in preparation 14, ethyl2-ethoxy-3-(4-aminophenyl)propanoate (1.4 g, 1.0 eq, 5.9 mmol), obtainedin preparation 1, and anhydrous K₂CO₃ (2.45 g, 3.0 eq, 17.7 mmol) in dryDMF (30 ml) was stirred at RT for 2 days. The reaction was diluted withethyl acetate (100 ml) and washed with water and brine. The organiclayer was dried. (Na₂SO₄), condensed, and the residue waschromatographed using ethyl acetate and hexane to obtain the titlecompound as viscous liquid (500 mg, 20% yield).

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=6.8 Hz, 3H), 1.23 (t, J=6.6 Hz,3H), 1.27 (bs, 1H, N—H), 1.94 (quintet, 6.8 Hz, 2H) 2.90 (d, J=6.9 Hz,2H), 3.03 (t, J=4.8 Hz, 2H), 3.20 (t, J=6.9 Hz, 2H), 3.20-3.45 (m, 3H),3.45-3.64 (m, 3H), 3.95 (t, J=6.4 Hz, 1H), 4.16 (q, J=6.9 Hz, 2H),6.50-6.72 (aromatics, 4H), 6.90-7.10 (aromatics, 4H).

IR (neat) cm⁻¹: 3398, 2926, 1742, 1616.

Mass m/z (CI): 428 [M], 429 [M+1].

EXAMPLE 262-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b]1,4]thiazin-4-yl)propylamino}phenyl]propanoicacid

Ethyl2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate(250 mg, 1.0 eq, 0.58 mmol), obtained in example 25, was hydrolyzed bytreating with LiOH.H₂O (74 mg, 3 eq, 1.75 mmol) in MeOH-THF-watersolvent mixture at RT for 3-4 h. The reaction mixture was condensed,diluted with water and acidified (pH at 4) with aq. HCl. Finally thecrude acid was extracted with ethyl acetate. The ethyl acetate layer wasdried (Na₂SO₄), condensed, and chromatographed using MeOH and CHCl₃ aseluent to obtain the title compound as thick liquid (152 mg, 68% yield).

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=6.9 Hz, 3H), 1.26 (bs, 1H, N—H);1.93 (quintet, 6.9 Hz, 2H), 2.85-3.10 (m, 4H), 3.02 (t, J=5.1 Hz, 2H),3.19 (t, J=6.9 Hz, 2H); 3.20-3.65 (m, 4H), 4.02 (dd, J=6.9, 4.4 Hz, 1H),4.70 (bs, 1H, CO₂H), 6.50-6.72 (aromatics, 4H), 6.90-7.10 (aromatics,4H).

IR (neat) cm⁻¹: 3411, 2929, 1726, 1616.

Mass m/z (CI): 400 [M], 401 [M+1].

EXAMPLE 272-Ethoxy-3-[4-{3-3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoicacid arginine salt

A mixture of2-ethoxy-3-[4-{3-3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoicacid (110 mg, 1 eq, 0.27 mmol), obtained in example 26, and L-arginine (47.9 mg, 1 eq, 0.27 mmol) was taken in dry MeOH (2.0 ml) was stirred atRT for 2 h to get a clear solution. The solvent was condensed, theresidue was azeotroped with dry benzene and dried over vacuum pump toobtain the title compound as a solid mass (100% yield), mp: 142-144° C.

EXAMPLE 28 Ethyl2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4yl)ethylamino}phenyl]propanoate

A mixture of 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylbromide(940 mg, 1 eq, 3.8 mmol), obtained in preparation 15, ethyl2-ethoxy-3-(4-aminophenyl)propanoate (1.0 g, 1.1 eq, 4.2 mmol), obtainedin preparation 1, anhydrous K₂CO₃ (1.6 g, 3 eq, 10.8 mmol) andtetrabutylammonium bromide (265 mg, 0.2 eq, 0.8 mmol) in dry toluene (20ml) was heated at 90° C. for 24 h. The reaction mixture was diluted withethyl acetate and the organic layer was washed with water, brine, thendried (Na₂SO₄), and condensed. The residue was chromatographed withethyl acetate and hexanes as eluents to obtain the desired product asthick liquid (960 mg, 60%).

¹H NMR (200 Mz, CDCl₃) δ: 1.17 (t, J=6.9 Hz, 3H), 1.23 (t, J=6.6 Hz,3H), 1.27 (bs, 1H, N—H), 2.90 (d, J=6.4 Hz, 2H), 3.20-3.65 (m, 8H), 3.95(t, J=6.4 Hz, 1H), 4.05-4.25 (m, 4H), 6.56 (d, J=8.3 Hz, 2H), 6.60-6.85(aromatics, 4H), 7.06 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3395, 2977, 1740, 1616.

Mass m/z (CI): 398 [M], 399 [M+1].

EXAMPLE 292-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoicacid

Ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate(960 mg, 1.0 eq, 2.41 mmol), obtained in example 28, was hydrolyzed bytreating with LiOH.H₂O (350 mg, 3 eq, 7.2 mmol) in MeOH-THF-watersolvent mixture at RT for 3-4 h. The reaction mixture was condensed,diluted with water and acidified (pH at 4-5) with aq. HCl. Finally thecrude acid was extracted with ethyl acetate. The ethyl acetate layer wasdried (Na₂SO4), condensed, and chromatographed using MeOH and CHCl₃ aseluents to obtain the desired compound as thick liquid (370 mg, 42%).

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=6.8 Hz, 3H), 1.21 (bs, 1H, N—H),2.90 (dd, J=14, 8 Hz, 1H), 3.03 (dd, J=14, 4.3 Hz, 1), 3.20-3.65 (m,8H), 4.02 (dd, J=6.49, 4.4 Hz, 1H), 4.21 (t, J=4.4 Hz, 2H), 5.00 (bs,CO₂H), 6.58 (d, J=8.3 Hz, 2H), 6.60-6.85 (aromatics, 4H), 7.06 (d, J=8.3Hz, 2H).

IR (neat) cm⁻¹: 3383 (br), 2927, 1727, 1607.

Mass m/z (CI): 371 [M+1].

EXAMPLE 302-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl}propanoicacid arginine salt

The title compound was prepared as a free flowing solid (mp: 142-144°C.) from2-ethoxy-3-[4-{2-(3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoicacid, obtained in example 29 and L-arginine, by following the similarprocedure as described for example 27.

EXAMPLE 31 Methyl2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate

A mite of 4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}aniline(305 mg, 1 eq, 1.13 mmol) obtained in preparation 16, methyl2-ethoxy-3-(4-formylphenyl)propanoate (267 mg, 1 eq, 1.13 mmol),obtained in preparation 5, activated molecular sieves (4 A), and p-TsOH(21 mg, 0.1 eq, 0.11 mmol) in dry DCM (4 ml) were stirred at RT for 16h. The reaction mixture was diluted with ethylacetate (100 ml), washedwith aq. sodium bicarbonate, dried (Na₂SO₄), and condensed. The crudemass was dissolved in dry methanol (6 ml) and conc HCl (125 μL) wasadded at 0° C., followed by NaB(CN)H₃ (118 mg, 1.5 eq, 1.87 mmol) inportions. The reaction mixture was stirred at 0° C. for 3 h, after thatit was diluted with ethyl acetate (100 ml). The organic layer was washedwith aq. sodium bicarbonate, dried (Na₂SO₄), and condensed. The residuewas chromatographed using ethyl acetate and hexanes to obtain the titlecompound as thick oil (525 mg, 85%).

¹H (200 MHz, CDCl₃) δ:1.16 (t, J=6.9 Hz, 3H), 1.25 (bs, —NH—), 3.00 (d,J=6.8, 2H), 3.22-3.42 (m, 1H), 3.49 (t, J=4.4 Hz, 2H), 3.55-3.75 (m,3H), 3.71 (s, 3H), 3.99-4.12 (m, 3H), 4.15-4.24 (m, 4H), 6.50-6.90(aromatics, 8H), 7.19 (d, J=7.8, 2H), 7.28 (d, J=8.0, 2H).

IR (neat) cm⁻: 3405 (br), 2927, 146, 1606.

Mass m/z (CI): 490 [M], 491 [M+1].

EXAMPLE 322-Ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoicacid

Methyl2-ethloxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b]1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate(520 mg, 1.0 eq, 1.06 mmol), obtained in example 31, was hydrolyzed bytrain with LiOH.H₂O (134 mg, 3 eq, 3.18 mmol) in MeOH-THF-water solventmixture at RT for 3-4 h. The reaction mixture was condensed, dilutedwith water and acidified (pH at 4) with aq. HCl. Finally the crude acidwas extracted out by ethyl acetate. The ethyl acetate layer was dried(Na₂SO₄), condensed, and chromatographed using MeOH and CHCl₃ as eluentsto obtain the desired compound as thick liquid (150 mg, 30%).

¹H NMR (200 MHz, CDCl₃) δ: 1.18 (t, J=6.9 Hz, 3H), 1.29 (bs, —NH—),2.90-3.20 (m, 2H), 3.22-3.75 (m, 6H), 4.00-4.18 (m, 3H), 4.20-4.25 (m,4H), 6.00 (bs, CO₂H), 6.60-6.90 (aromatics, 8H), 7.24 (d, J=8.3, 2H),7.29 (d, J=8.3, 2H).

IR (neat) cm⁻¹: 3390 (br), 2927, 1725, 1605.

Mass m/z (CI): 476 [M], 477 [M+1].

EXAMPLE 332-Ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoicacid arginine salt

A mixture of2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoicacid (110 mg, 1 eq, 0.23 mmol), obtained in example 32, and L-arginine(40 mg, 1 eq, 0.23 mmol) taken in dry MeOH (2 ml) was stirred at RT for2 h to get a clear solution. The solvent was condensed, the residue wasazeotroped with dry benzene and dried over vacuum pump to obtain a solidmass (100% yield), mp: 154-156° C.

EXAMPLE 34[2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide

To a solution of racemic2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoicacid (2.0 g, 1.0 eq, 5.20 mmol) obtained in example 2, in DCM (26 ml)and triethylamine (3.61 ml, 5 eq, 26 mmol), isobutylchloroformate (1.35ml, 2 eq, 10.4 mmol) was added dropwise at 0 ° C. The reaction mixturewas stirred at RT for 30 min followed by addition of (R)-phenylglycinol(1.42 g, 2 eq, 10.4 mmol). The reaction mixture was further stirred atRT for 16 h, which was then diluted with DCM, washed with water andbrine, dried (Na₂SO₄), and codensed. The residue was chromatographedusing ethyl acetate and hexane to obtain the title compound as fastermoving (S, R)-diastereomer (620 mg, 23.7% yield), follolwed byrelatively slower moving (R, R)-diastereomer, (630 mg, 24% yield), bothas viscous liquid. Characterization of (R, R)-diastereomer is describedin example 35.

¹H NMR (200 MHz, CDCl₃) δ: 1.14 (t, J=6.8 H, 3H), 1.24 (s, 1H), 1.91(quintet, J=6.8 Hz, 2H), 2.90 (dd, J=12 and 5.8 Hz, 1H), 3.06 (dd, J=12and 3.9 Hz, 1H), 3.19 (t, J=6.8 Hz, 2H), 3.25-3.60 (m, 6H), 3.60-3.70(m, 2H), 3.97 (dd, J=5.8 and 3.9 Hz, 1H), 4.22 (t, J=4.4 Hz, 2H),4.88-5.00 (m, 1H), 6.50-7.40 (aromatic and amide-NH, 14H).

IR (neat) cm⁻¹: 3393 (br), 2.927, 1660.

Mass m/z (CI): 503 [M], 504 [M+1].

EXAMPLE 35[2R,N(1R)-N-(2-hydroxy-1phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]proanamide

The title compound is obtained by following the similar proceduredescribed in example 34.

¹H NMR (200 MHz, CDCl₃) δ: 1.16 (t, J=6.8 Hz, 3H), 1.24 (s, 1H), 1.91(quintet, J=6.8 Hz, 2H), 2.80 (dd, J=14, 7.5 Hz, 1H), 3.06 (dd, J=14,3.9 Hz, 1H), 3.17 (t, J=6.8 Hz, 2H), 3.25-3.60 (m, 6H), 3.78-3.90 (m,2H), 3.89 (dd, J=7.5, 3.9 Hz, 1H), 4.22 (t, J=4.4 Hz, 2H), 4.88-5.00 (m,1H), 6.45-7.35 (aromatics and amide-NH, 14H).

IR (neat) cm⁻¹: 3399 (br), 2927, 1660.

Mass m/z (CI): 503 [M], 504 [M+1].

EXAMPLE 36[2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamidehydrochloride salt

To a dry methanolic HCl solution (2 ml)[2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide(95 mg, 0.19 mmol) obtained in example 34, was added and the mixture wasstirred at RT for 5 min. Then the reaction mixture was condensed andazeotroped using dry benzene on rotary evaporator. The residue was driedon high-vacuum to obtain the title compound as a brown solid mass (100%yield, mp: 74-75 ° C.).

EXAMPLE 37[2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamidehydrochloride salt

To a dry methanolic HCl solution (2 ml)[2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide(95 mg, 0.19 mmol) obtained in example 35, was added and the mixture wasstirred at RT for 5 min. Then the reaction mixture was condensed andazeotroped using dry benzene on rotary evaporator. The residue was driedon high-vacuum to obtain the title compound as a brown solid mass (100%yield, mp: 69-70 ° C.).

EXAMPLE 382-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoicacid magnesium salt

A mixture of methanolic solution (2 ml) of2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoicacid (75 mg, 1 eq, 0.19 mmol) obtained in example 2 and magnesiumhydroxide (5.6 mg, 0.5 eq, 0.095 mmol) was heated at 50° C. for 5 h. Theresulting solution was condensed, azeotroped with benzene and thenfinally dried on high vacuum pump to obtain the title compound as freedflowing solid (100% yield, mp: 132-134° C.).

EXAMPLE 39[2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide

To a solution of racemic2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoicacid (1.8 g, 1.0 eq, 4.48 mmol) obtained in example 17, in DCM (25 ml)and triethylamine (2.49 ml, 4 eq, 17.92 mmol); isobutylchloroformate(875 μL, 1.5 eq, 6.72 mmol) was added dropwise at 0° C. The reactionmixture was stirred at RT for 30 min followed by addition of(R)-phenylglycinol (1.23 g, 2 eq, 8.96 mmol). The reaction mixture wasfurther stirred at RT for 16 h, which was then diluted with DCM, washedwith water and brine, dried (Na₂SO₄), and condensed. The residue waschromatographed using ethyl acetate and hexane to obtain the titlecompound as faster moving (S, R)-diastereomer (370 mg, 32 % yield),followed by relatively slower moving (R, R)-diastereomer, (370 mg, 32 %yield), both as viscous liquid. Characterization of (R, R)-diastereomeris described in example 40 (next example).

[α]_(D): −7.0° (c, 1.0 CHCl₃).

¹H NMR (200 MHz, CDCl₃) δ: 1.16 (t, J=6.8 Hz, 3H), 1.92 (quintet, J=6.8Hz, 2H), 2.92 (dd, J=14, 5.6 Hz, 1H), 3.08 (dd, J=14, 3.5 Hz, 1H), 3.22(t, J=6.4 Hz, 2H), 3.20-3.40 (m, 4H), 3.40-3.80 (m, 4H), 3.99 (t, J=5.2Hz, 1H), 4.23 (t, J=4.4 Hz, 2H), 4.88-5.02 (m, 1H), 6.40-6.60 and6.90-7.40 (aromatics and amide-NH, 13H).

IR (neat) cm⁻¹: 3405 (br), 2933, 1660, 1615, 1514.

Mass m/z (CI): 521 [M], 522 [M+1].

EXAMPLE 40[2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide

The title compound is obtained during syntheis of example 39 as anotherdiastereomer (R, R).

[α]_(D): 17.4° (c, 1.0 CHCl₃).

¹H NMR (200 MHz, CDCl₃) δ: 1.18 (t, J=6.8 Hz, 3H), 1.91 (quintet, J=6.8Hz, 2H), 2.51 (bs, NH, OH); 2.82 (dd, J=14.2 and 7.3 Hz, 1H), 3.04 (dd,J=14.2 and 3.4 Hz, 1H), 3.20 (t, J=6.4 Hz, 2H); 3.25-3.40 (m, 4H),3.42-3.70 (m, 2H), 3.80-3.90 (m, 2H); 3.98 (dd, J=7.3 and 4.0 Hz, 1H),4.24 (t, J=4.8 H, 2H), 4.88-5.2 (m, 1H), 6.4-6.60 and 7.00-7.40(aromatic and amide-NH, 13H).

IR (neat) cm^(−1:) 3398 (br), 2929, 1660, 1616, 1513.

Mass m/z (CI): 521 [M], 522 [M+1].

EXAMPLE 41[2S,N(1R)]-N-(2-hydroxy-1-phenylethyl-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamidehydrochloride salt

To a dry methanolic HCl solution (2 ml)[2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b](1,4]oxazin-4-yl)propylamino}phenyl]propanamide(95 mg, 0.19 mmol) obtained in example 34, was added and the mixture wasstirred at RT for 5 min. Then the reaction mixture was condensed andazeotroped using dry benzene on rotary evaporator. The residue was driedon high-vacuum to obtain the title compound as a brown solid mass (100%yield, top: 74-75° C.).

EXAMPLE 42[2R,N(1R)]-N-(2-hydroxy-1-phenylethyl-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamidehydrochloride salt

To a dry methanolic HCl solution (2 ml)[2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide(95 mg, 0.19 mmol) obtained in example 35, was added and the mixture wasstirred at RT for 5 min. Then the reaction mixture was condensed andazeotroped using dry benzene on rotary evaporator. The residue was driedon high-vacuum to obtain the title compound as a brown solid mass (100%yield, mp: 69-70° C.).

EXAMPLE 43(−)-(S)-3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid

[α]_(D): −17° (c, 1.0 MeOH).

¹H NMR (200 MHz, CDCl₃) δ: 1.19 (t, J=7.4Hz, 3H), 1.94 (q, J=7.4Hz, 2H),2.90 (dd, J=14.0 and 7.0 Hz, 1H), 3.05 (dd, J=14.0 and 4.9Hz, 1H), 3.21(t, J=6.8 Hz, 2H), 3.25-3.40 (m, 5H), 3.40-3.62, (m, 1H), 4.00-4.17 (m,1H), 4.18-4.22 (m, 2H), 6.59 (d, J=8.3 Hz, 2H), 6.65-6.85 (m, 4H), 7.06(d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹:3500, 1725.

Mass m/z (CI): 385 (M+1).

EXAMPLE 44(+)-(R)-3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid

[α]_(D): 16.8° (c, 1.0 MeOH).

¹H NMR (200 MHz, CDCl₃) δ: 1.19 (t, J=7.4 Hz, 3H), 1.94 (q, J=7.4 Hz,2H), 2.90 (dd, J=14.0 and 7.0 Hz, 1H, 3.05 (dd, J=14.0 and 4.9 Hz, 1H),3.21 (t, J=6.8 Hz, 2H), 3.25-3.40 (m, 5H), 3.40-3.62 (m, 1H), 4.00-4.17(m, 1H), 4.18-4.22(m, 2H), 6.59 (d, J=8.3 Hz, 2H), 6.65-6.85 (m, 4H),7.06 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹:38500, 1125.

Mass m/z (CI): 385 (M+1).

EXAMPLE 45 Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)pryopylamino}phenyl]-2-ethoxypropanoate

(S)-Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (2.20 g, 1 eq, 9.28 mmol)obtained in preparation 20,3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (3.30g, 1.3 eq, 12.06 mmol) obtained in preparation 10, and anhydrous K₂CO₃(3.84 g, 3 eq, 27.84 mmol), and tetrabutyl ammonium bromide (597 mg, 0.2eq., 1.85 mmol) were heated at 90° C. in dry toluene (47 mL) for 20 h.The reaction time was diluted with ethyl acetate, washed with water andbrine. The residue was chromatographed using ethyl acetate and hexane toafford the title compound (1.78 g, yield 44.5%) as viseous liquid.

[α]_(D): −9.20 (c 1.0, MeOH).

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=7 Hz, 3H), 1.23 (t, J=7 Hz, 3H),1.89 (q, J=6.8 Hz, 2H), 2.90 (d, J=6.5 Hz, 2H), 3.10-3.42 (m, 7H),3.45-3.65 (m, 1H), 3.95 (t, J=6.7 Hz, 1H), 4.10-4.30 (m, 4H), 6.40-6.70(m, aromatics, 5H), 7.05 (d, J=8.4 Hz, 2H).

IR (neat) cm^(−1:) 3394 (br), 2978, 1740, 1617, 1514.

Mass m/z (CI): 431 (M+1).

EXAMPLE 46(S)-3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid

(S)-Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate(1.7 g, 1 eq, 3.95 mmol) obtained in example 45, was hydrolyzed usinglithium hydroxide monohydrate (249 mg, 1.5 eq, 5.93 mmol), inmethanol-THF-water at RT till all the starting material is consumed (4to 5 h). The reaction mixture was diluted with water, acidified (pH˜4-5) with dil. HCl and then extracted with ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate and concentratedon rotary evaporator. The residue was chromatographed using ethylacetate and hexanes→methanol and chloroform to afford the title compound(1.5 g, yield 94%) as viscous liquid.

[α]_(D): −16.1° (c 1.0, MeOH).

Chiral HPLC: >98 % ee.

¹H NMR (200 MH, CDCl₃) δ: 1.19 (t, J=7.4 Hz, 3H), 1.94 (quintet, J=7.4Hz, 2H), 2.85-3.10 (m, 2H), 3.10-3.20 (m, 6H), 3.40-3.70 (m, 2H),3.90-4.10 (m, 1H), 4.10-4.30 (m, 2H), 6.20 (bs, NH, CO₂H), 6.42-6.70 (m,aromatics, 5H), 7.07 (d, J=8.3 Hz, 2H).

IR (KBr) cm^(−1:) 3394, 1725, 1619.

Mass m/z (CI): 403 (M+1).

EXAMPLE 47(S)-3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid L-arginine salt

(S)-3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid (300 mg, 1 eq, 0.74 mmol) obtained in example 46, and L-arginine(130 mg, 1 eq, 0.74 mmol) were taken in dry methanol (4 ml), and stirredat RT for 2-3 h. The solvent was removed on rotavapour followed bybenzene azeotrope. The residue was dried under high vacuum pump to yieldthe title compound as a free following solid (yield 100%).

Mp: 114-116° C.

EXAMPLE 48(S)-3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo-[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-exthoxypropanoicacid magnesium salt

(S)-3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo-[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-exthoxypropanoicacid (1.13 g, 1.0 eq, 2.81 mmol), obtained in example 46, in dry ethanol(15 mL) was treated with Mg(OMe)₂ (121 mg, 0.5 eq, 1.4 mmol). Theresulting mixture was heated at 55-60° C. for 7-8 h. The reactionmixture was condensed on rotavapour, azeotroped with benzene, andfinally dried on high vacuum pump. The sticky mass was triturated withhexanes to obtain the desired salt as a powdery solid (quantitativeyield).

Mp: 240-242° C. (dec.).

EXAMPLE 49 Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate

(S)-Ethyl 2-methoxy-3-(4-aminophenyl)propanoate (800 mg, 1.0 eq, 3.58mmol) obtained in preparation 21,3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (1.27g, 1.3 eq, 4.65 mmol) obtained in preparation 10, and anhydrous K₂CO₃(1.48 g, 3 eq, 10.79 mmol), and tetrabutyl ammonium bromide (576 mg, 0.5eq., 1.79 mmol) were heated at 90° C. in dry toluene (20 mL) for 9 h.The reaction mixture was diluted with ethyl acetate, washed with waterand brine. The residue was chromatographed using ethyl acetate andhexane to afford the title compound (1.1 g, yield 73%) as viscousliquid.

[α]_(D): 4.0° (c 1.0, MeOH).

¹H NMR (200 MHz, CDCl₃) δ: 1.25 (t, J=7.3 Hz, 3H), 1.89 (q, J=7.0 Hz,2H), 2.91 (d, J=6.0 Hz, 2H), 3.05-3.42 (m, 6H), 3.36 (s, 3H); 3.90 (t,J=6.4 Hz, 1H), 4.10-4.30 (m, 4H), 6.40-6.70 (m, aromatics, 5H), 7.05(aromatics, 2H).

IR (neat) cm⁻¹: 3385 (br), 2934, 1741, 1617, 1514.

Mass m/z (CI): 417 (M+1).

EXAMPLE 50(S)-3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid

(S)-Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate(1.0 g, 1 eq, 2.4 mmol) obtained in example 49, was hydrolyzed usinglithium hydroxide monohydrate (151 mg, 1.5 eq, 3.6 mmol) inmethanol-THF-water at RT till all the starting material is consumed (4to 5 h). The reaction mixture was diluted with water, acidified (pH˜4-5) with dil. HCl and then extracted with ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate and concentratedon rotary evaporator. The residue was chromatographed using ethylacetate and hexanes→methanol and chloroform to afford the title compound(650 mg, yield 70%) as viscous liquid.

[α]_(D): −14.2° (c 1.0, MeOH).

Chiral HPLC: >98% ee.

¹H NMR (200 MHz, CDCl₃) δ: 1.9 (quintet, J=7.4 Hz, 2H), 2.85-3.10 (m,2H), 3.10-3.38 (m, 6H), 3.40 (s, 3H); 3.90-4.05 (m, 1H); 4.24 (t, J=4.2Hz, 2H); 6.42-6.70 (m, aromatics, 5H); 7.05 (d, J=8.0 Hz, 2H).

IR (neat) cm⁻¹: 3396, 2936, 1727, 1614, 1513.

Mass m/z (CI): 389 (M+1).

EXAMPLE 51(S)-3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid magnesium salt

(S)-3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid (400 mg, 1.0 eq, 1.03 mmol), obtained in example 50, in drymethanol (5 mL) was treated with Mg(OMe)₂ (44.3 mg, 0.5 eq, 0.51 mmol).The resulting mixture was heated at 55-60° C. for 7-8 h. The reactionmixture was condensed on rotavapour, azeotroped with benzene, andfinally dried on high vacuum pump. The sticky mass was triturated withhexanes to obtain the desired salt as a powdery solid (quantitativeyield).

Mp: 210-212° C. (dec.).

EXAMPLE 52 Ethyl3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (500 mg, 1 eq, 2.11 mmol)obtained in preparation 1,3-(2-methyl-7-fluoro-3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide(670 mg, 1.1 eq, 2.32 mmol) obtained in preparation 17, and anhydrousK₂CO₃ (875 mg, 3 eq, 6.33 mmol), and tetrabutyl ammonium bromide (340mg, 0.5 eq., 1.05 mmol) were heated at 90° C. in dry toluene (11 mL) for12 h. The reaction mixture was diluted with ethyl acetate, washed withwater and brine. The residue was chromatographed using ethyl acetate andhexane to afford the title compound (320 mg, yield 32%) in the form ofmixture of diastereomers as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.10-1.25 (m, 9H), 1.80-2.00 (m, 2H),2.82-3.02 (m, 2H), 3.10-3.50 (m, 2H), 3.28-3.44 (m, 3H), 3.50-3.65 (m,1H); 3.90-4.00 (m, 1H), 4.10-4.30 (m, 3H), 6.40-6.80 (aromatics, 5H),7.00-7.20 (aromatics, 2H).

IR (neat) cm^(−1:) 3389 (br), 2929, 1740, 1617, 1515.

Mass m/z (CI): 445 (M+1).

EXAMPLE 533-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid

Ethyl3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate(320 mg, 1 eq, 0.72 mmol) obtained in example 52, was hydrolyzed usinglithium hydroxide monohydrate (46 mg, 1.5 eq, 1.08 mmol), inmethanol-THF-water at RT till all the starting material is consumed (4to 5 h). The reaction mixture was diluted with water, acidified (pH˜4-5) with dil. HCl and then extracted with ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate and concentratedon rotary evaporator. The residue was chromatoghaphed using methanol andchloroform to afford the title compound (190 mg, yield 64%) as viscousliquid.

¹H NMR (200 Mz, CDCl₃) δ: 1.21 (t, J=7.1 Hz, 3H), 1.36 (d, J=6.4 Hz,3H), 1.92 (quintet, J=6.8 Hz, 2H), 2.90-3.10 (m, 2H), 3.10-3.40 (m, 6H),3.42-3.60 (m, 2H); 4.06 (dd, J=6.8, 3.9 Hz, 1H), 4.20-4.35 (m, 1H);6.50-6.62 (aromatics, 5H), 7.07 (d, J=8.3 Hz, 2H).

IR (KBr) cm^(−1:) 3387, 2927, 1726, 1,615, 1514.

Mass m/z (CI): 417 (M+1).

EXAMPLE 543-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid magnesium salt

3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid (170 mg, 1.0 eq, 0.41 mmol), obtained in example 53, in drymethanol (5 mL) was treated with Mg(OMe)₂ (17.6 mg, 0.5 eq, 0.21 mmol).The resulting mire was heated at 55-60° C. for 7-8 h. The reactionmixture was condensed on rotavapour, azeotroped with benzene, andfinally dried one high vacuum pump. The sticky mass was triturated withhexanes to obtain the desired salt as a powdery solid (quantitativeyield).

Mp: 110-112° C.

EXAMPLE 55 Ethyl3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Starting from ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (438 mg, 1 eq,1.85 mmol) obtained in preparation 1, and3-(2-methyl-3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (550mg, 1.1 eq, 2.32 mmol) obtained in preparation 18, and following theprocedure of example 52 the title compound (300 mg, yield 35%) wasobtained in the form of mixture of diastereomers as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=7.0 Hz, 3H); 1.23 (t, J=7.0 Hz,3H); 1.35 (d, J=6.4 Hz, 3H); 1.80-2.00 (m, 2H), 2.91 (d, J=6.7 Hz, 2H);3.00-3.42 (m, 7H); 3.45-3.65 (m, 1H); 3.95 (t, J=6.7 Hz, 1H), 4.10-4.30(m, 3H), 6.53 (d, J=8.3 Hz, 2H); 6.65 (t, J=7.8 Hz, 2H); 6.79 (d, J=7.8Hz, 2H); 7.06(d, J=8.3 Hz, 2H).

IR (neat) cm^(−1:) 3400 (br), 2976, 1741, 1616, 1520.

Mass m/z (CI): 427 (M+1).

EXAMPLE 563-[4-{3-(2-methyl-3,4dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid

Ethyl3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b]]1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoyxypropanoate(300 mg, 1 eq, 0.72 mmol), obtained in example 55 was hydrolyzedfollowing the procedure of example 53 to obtain the title compound (170mg, yield 61%) as viscouis liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=7.6 Hz, 3H); 1.34 (d, J=6.1 Hz,3H); 1.80-2.00 (m, 2H), 2.80-3.70 (m, 10H); 4.02 (dd, J=7.3, 4.5 Hz,1H), 4.10-4.30 (m, 1H), 5.6 (bs, 2H, CO₂H, NH); 6.55 (d, J=8.3 Hz, 2H);6.64 (t, J=7.8 Hz, 2H); 6.79 (d, J=7.8 Hz, 2H); 7.06 (d, J=8.3 Hz, 2H).

IR (KBr) cm⁻¹: 3393, 2974, 1726, 1617, 1503.

Mass m/z (C): 399 (M+1).

EXAMPLE 573-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid magnesium salt

From3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2ethoxypropanoicacid (155 mg, 1.0 eq, 0.39 mmol), obtained in example 56 and Mg(OMe)₂(16.5 mg, 0.5 eq, 0.20 mmol) the desired salt as a powdery solid(quantitative yield) following the procedure of example 54.

Mp: 102-104° C.

EXAMPLE 58 Ethyl(2S)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate

Starting from ethyl (S)-2-methoxy-3-(4-aminophenyl)propanoate (500 mg, 1eq, 2.24 mmol) obtained in preparation 21, and3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (666mg, 1.1 eq, 2.47 mmol) obtained in preparation 18, and following theprocedure of example 52, the title compound (340 mg, yield 38%) wasobtained in the form of mixture of diastereomers as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.25 (t, J=7.2 Hz, 3H); 1.36 (d, J=6.4 Hz,3H); 1.80-2.00 (m, 2H), 2.92 (d, J=6.2 Hz, 2H); 3.02-3.50 (m, 9H); 3.90(t, J=6.9 Hz, 1H), 4.10-4.30 (m, 3H), 6.54 (d, J=8.3 Hz, 2H); 6.65 (t,J=7.2 Hz, 2H); 6.80 (d, J=7.2 Hz, 2H); 7.05 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3398 (br), 2928, 1741, 1613, 1520.

Mass m/z (CI): 413 (M+1).

EXAMPLE 59(2S)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid

Ethyl(2S)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate(170 mg, 1 eq, 0.413 mmol), obtained in example 58, was hydrolyzedfollowing the procedure of example 53, to obtain the title compound (100mg, yield 63%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.35 (d, J=6.5 Hz, 3H); 1.80-2.00 (m, 2H),2.85-3.60 (m, 11H); 3.98 (dd, J=7.0, 4.3 Hz, 1H), 4.15-4.30 (m, 1H),6.55 (d, J=8.3 Hz, 2H); 6.65 (t, J=7.2 Hz, 2H); 6.79 (d, J=7.2 Hz, 2H);7.05 (d, J=8.3 Hz, 2H).

IR (KBr) cm^(−1:) 3391, 2930, 1727, 1608, 1506.

Mass m/z (CI): 385 (M+1).

EXAMPLE 60(2S)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid magnesium salt

From(2S)-3-[4-{3-[4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid (90 mg, 1.0 eq, 0.23 mmol), obtained in example 59, and Mg(OMe)₂(10.1 mg, 0.5 eq, 0.12 mmol) the desired salt as a powdery solid(quantitative yield) following the procedure of example 54.

Mp: 160-162° C.

EXAMPLE 61 Ethyl3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl}-2-ethoxypropanoate

Starting from ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (325 mg, 1 eq,1.37 mmol) obtained in preparation 1, and3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (450mg, 1.1 eq, 1.51 mmol) obtained in preparation 19, and following theprocedure of example 52, the title compound (343 mg, yield 69%) wasobtained in the form of mixture of diastereomers as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 0.97 (t, J=7.0 Hz, 3H); 1.17 (t, J=7.2 Hz,3H); 1.22 (t, J=7.3 Hz, 3H); 1.40-1.80 (m, 4H); 1.91 (quintet, J=6.7 Hz,2H1), 2.90 (d, J=6.4 Hz, 2H); 3.00-3.42 (m, 7H); 3.45-3.65 (m, 1H); 3.94(t, J=6.4 Hz, 1H), 4.00-4.22 (m, 3H), 6.52 (d, J=8.3 Hz, 2H); 6.64 (t,J=7.0 Hz, 2H); 6.78 (d, J=7.2 Hz, 2H); 7.05 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3400 (br), 2959, 1741, 1616, 1520.

Mass m/z (CI): 455 (M+1).

EXAMPLE 623-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid

Ethyl3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate(305 mg, 1 eq, 0.67 mmol), obtained in example 61, was hydrolyzedfollowing the procedure of example 53 to obtain the title compound (177mg, yield 62%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 0.97 (t, J=7.0 Hz, 3H); 1.18 (t, J=7.2 Hz,3H); 1.40-1.80 (m, 4H); 1.92 (quintet, J=6.7 Hz, 2H), 2.80-3.62 (m, 10H); 3.95-4.15 (m, 2H); 4.60 (bs, 2H); 6.55 (d, J=8.3 Hz, 2H); 6.64 (t,J=7.0 Hz, 2H); 6.79 (d, J=7.2 Hz, 2H); 7.06 (d, J=8.3 Hz, 2H).

IR (KBr) cm⁻¹: 3500, 2931, 1724, 1606, 1504.

Mass m/z (ES): 427 (M+1), 853 (M₂+1).

EXAMPLE 633-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid magnesium salt

From,3-[4-{3-(2-propyl-7-3,4-dihydro-2H-benzo[b]1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid (164 mg, 1.0 eq, 0.39 mmol), obtained in example 62, and Mg(OMe)₂(16.5 mg, 0.5 eq, 0.20 mmol) the desired salt as a powdery solid(quantitative yield) following the procedure of example 54.

Mp: 104-106° C.

EXAMPLE 64 Ethyl(2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl}-2-methoxypropanoate

Starting from ethyl (S)-2-methoxy-3(4-aminophenyl)propanoate (312 mg, 1eq, 1.1.40 mmol) obtained in preparation 21, and3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (460mg, 1.1 eq, 1.54 mmol) obtained in preparation 19, and following theprocedure of example 52, the title compound (255 mg, yield 69%) wasobtained in the form of mixture of diastereomers as viscous liquid.

¹H NMR (400 MHz, CDCl₃) δ: 0.99 (t, J=6.8 Hz, 3H); 1.26 (t, J=7.2 Hz,3H); 1.47-1.61 (m, 3H); 1.69-1.74 (m, 1H); 1.89-1.97 (m, 2H), 2.92 (d,J=4.0 Hz, 1H); 2.93 (d, J=2.0 Hz, 1H); 3.09 (dd, J=11.2, 7.8 Hz, 1H);3.18-3.30 (m, 3H; 3.36 (s, 3H); 3.31-3.48 (m, 2H); 3.90 (t, J=6.0 Hz,1H), 4.06-4.10 (m, 1H), 4.19 (q, J=7.2 Hz, 2H); 6.54 (d, J=8.8 Hz, 2H);6.55-6.65 (aromatics, 2H); 6.79 (d, J=7.2 Hz, 2H); 7.04 (d, J=8.8 Hz,2H).

IR (neat) cm⁻¹: 3396 (br), 2930, 1741, 1613, 1518.

Mass m/z (CI): 441 (M+1).

EXAMPLE 65(2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid

Ethyl(2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate(240 mg, 1 eq, 0.55 mmol), obtained in example 64, was hydrolyzedfollowing the procedure of example 53 to obtain the title compound (164mg, yield 73%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 0.96 (t, J=7.0 Hz, 3H); 1.44-1.67 (m, 4H);1.91 (quintet, J=7.0 Hz, 2H), 2.90-3.33 (m, 8 H); 3.38 (s, 3H);3.92-4.06 (m, 2H); 4.60 (bs, 2H); 6.55-6.66 (aromatics, 4H); 6.78 (d,J=7.4 Hz, 2H); 7.06 (d, J=8.2 Hz, 2H).

IR (KBr) cm⁻¹: 3397, 2930, 1727, 1606, 1504.

Mass m/z (ES): 413 (M+1), 825 (M₂+1), 1237 (M₃+1).

EXAMPLE 66(S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid magnesium salt

From(2S)-3-[4-{3-(2-propyl-7-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid (140 mg, 1.0 eq, 0.34 mmol), obtained in example 65 and mg(OMe)₂(14.5 mg, 0.5 eq, 0.17 mmol) the desired salt as a powdery solid(quantitative yield) following the procedure of example 54.

Mp: 172-174° C.

EXAMPLE 67 Ethyl2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate

Starting from ethyl 2-isopropoxy-3-(4-aminophenyl)propanoate (650 mg, 1eq, 2.59 mmol) obtained in preparation 22 and3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (781mg, 1.1 eq, 2.85 mmol) obtained in preparation 10, and following theprocedure of example 52, the title compound (700 mg, yield 61%) wasobtained a viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 0.98 (d, J=6.2Hz, 3H); 1.16 (d, J=6.2 Hz,3H); 1.23 (t, J=7.2 Hz, 3H); 1.81-1.88 (m, 2H; 2.85-2.89 (m, 2H);3.17-3.24 (m, 4H); 3.33 (t, J=7.3 H, 2H); 3.40-3.60 (m, 1H); 3.99 (t,J=6.0 Hz, 1H), 4.11-4.23 (m, 4H), 6.48-6.55 (aromatics, 3H); 6.63 (d,J=8.3 Hz, 2H); 7.08 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3396 (br), 2939, 1729, 1615, 1514.

Mass m/z (CI): 445 (M+1).

EXAMPLE 682-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoicacid

Ethyl2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate(600 mg, 1 eq, 1.35 mmol), obtained in example 67, was hydrolyzedfollowing the procedure of example 53 to obtain the title compound (240mg, yield 43%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.01 (d, J=6.2 Hz, 3H); 1.16 (d, J=6.2 Hz,3H); 1.91(quintet, J=6.7 Hz, 2H); 2.84 (dd, J=14, 8.1 Hz, 1H); 3.00 (dd,J=14, 4.2 Hz, 1H); 3.16-3.34 (m, 6H); 3.42-3.60 (m, 1H); 4.06 (dd,J=8.1, 4.2 Hz, 1H), 4.20-4.25 (m, 2H), 6.09 (bs, 2H); 6.47-6.58(aromatics, 5H); 7.06 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3388 (br), 2932, 1722, 1616, 1513.

Mass m/z (CI): 417 (M+1).

EXAMPLE 692-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoicacid magnesium salt

From2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoicacid (240 mg, 1.0 eq, 0.57 mmol), obtained from example 68, and Mg(OMe)₂(25 mg, 0.5 eq, 0.29 mmol) the desired salt as a powdery solid(quantitative yield) following the procedure of example 54.

Mp: 110° C.

EXAMPLE 70 Ethyl(2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate

Starting from ethyl (S)-2-methoxy-3-(4-aminophenyl)propanoate (500 mg 1eq, 2.24 mmol) obtained in preparation 21 and3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide(711 mg, 1.1 eq, 2.47 mmol) obtained in preparation 17, and followingthe procedure of example 52, the title compound (380 mg, yield 40%) wasobtained in the form of mixture of diastereomers as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.20-1.40 (m, 6H); 1.80-2.00 (m, 2H),2.90-3.02 (m, 2H); 3.02-3.40 (m, 9H); 3.90 (t, J=6.3 Hz, 1H), 4.10-4.30(m, 3H), 6.40-6.60 (aromatics, 5H); 7.05 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3450 (br), 2926, 1740, 1611, 1515.

Mass m/z (CI): 431 (M+1).

EXAMPLE 71(2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid

Ethyl(2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate(380 mg, 1 eq, 0.88 mmol), obtained in example 70, was hydrolyzedfollowing the procedure of example 53, to obtain the title compound (150mg, yield 43%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.37 (d, J=6.2 Hz, 3H); 1.80-2.00 (m, 2H),2.90-3.60 (m, 13H); 3.98 (dd, J=7.0, 4.3 Hz, 1H), 4.18-4.35 (m, 1H),6.55-6.70 (aromatics, 5H); 7.10 (d, J=8.0 Hz, 2H).

IR (KBr) cm⁻¹: 3400 (br), 2930, 1729, 1614, 1513.

Mass m/z (ES): 403.3 (M+1), 805.5 (M₂+1).

EXAMPLE 72(2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid magnesium salt

From(2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid (150 mg, 1.0 eq, 0.37 mmol), obtained in example 71, and Mg(OMe)₂(16 mg, 0.5 eq, 0.185 mmol) the desired salt as a powdery solid(quantitative yield) following the procedure of example 54.

Mp: 208-210° C.

The compounds of the present invention lowered random blood sugar level,triglyceride, total cholesterol, LDL, VLDL and increased HDL. This wasdemonstrated by in vitro as well as in vivi animal experiments.

Demonstration of Efficacy of Compounds

A) In vitro:

a) Determination of hPPARα Activity

Ligand binding domain of hPPARα was fused to DNA binding domain of Yeasttranscription factor Gal 4 in eucaryotic expression vector. Usingsuperfect (Qiagen, Germany) as transfecting reagent HEK-293 cells aretransfected with this plasmid and a reporter plasmid harboring theluciferace gene driven by a GAL4 specific promoter. Compound can beadded at different concentrations after 42 hrs of transfection andincubated overnight. Luiciferase activity as a function of compoundbinding/activation capacity of PPARα will be measured using PackardLuclite kit (Packard, USA) in Top Count (Ivan Sadowsi, Brendan Bell,Peter Broag and Melvyn Hollis. Gene. 1992. 118: 137-141; SuperfectTransfetion Reagent Handbook February 1997. Qiagen, Germany.

b) Determination of hPPARγ Activity

Ligand binding domain of hPPARγ is fused to DNA binding domain of Yeasttranscription factor GAL4 in eucaryotic expression vector. Usinglipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293 cells aretransfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound can beadded at 1 μM concentration after 48 hrs of transfection and incubatedovernight Luciferase activity as a function of drug binding/activationcapacity of PPARγ1 will be measured using Packard Luclite kit (Packard,USA) in Packard Top Cout (Ivan Sadowski, Brendan Bell, Peter Broag andMelvyn Hollis. Gene. 1992. 118: 137-141; Guide to EukaryoticTransfections with Cationic Lipid Reagents. Life Technologies, GIBCOBRL, USA). Example No Concentration PPARα Concentration PPARγ  3 50 μM4.7 1 μM 3.0  9 50 μM 4.6 1 μM 6.2 18 50 μM 4.4 1 μM 1.2 23 50 μM 4.2 1μM 4.4 27 50 μM 4.3 1 μM 3.5

c) Determination of HMG CoA Reductase Inhibition Activity

Liver microsome bound reductase is prepared from 2% cholestyrarmine fedrats at mid-dark cycle. Spectrophotometric assays are carried out in 100mM KH₂PO₄, 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 μg of livermicrosomal enzyme. Total reaction mixture volume was kept as 1 ml.Reaction was started by addition of HMG CoA. Reaction mixture isincubated at 37° C. for 30 min and decrease in absorbance at 340 nm wasrecorded. Reaction mixture without substrate was used as blank(Goldstein, J. L and Brown, M. S. Progress in understanding the LDLreceptor and HMG CoA reductase, two membrane proteins that regulate theplasma cholesterol. J. Lipid Res. 1984, 25: 1450-1461). The testcompounds will inhibit the HMG CoA reductase enzyme.

B) In Vivo

a) Efficacy in Genetic Models

Mutation in colonies of laboratory animals and different sensitivitiesto dietary regimens have made the development of animal models withnon-insulin dependent diabetes and hyperlipidemia associated withobesity and insulin resistance possible. Genetic models such as db/dband ob/ob (Diabetes, (1982) 31(1): 1-6) mice and zucker fa/fa rats havebeen developed by the various laboratories for understanding thepathophysiology of disease and testing the efficacy of new antidiabeticcompounds (Diabetes, (1983) 32: 830-838; Annu. Rep. Sankyo Res. Lab.(1994). 46: 1-57). The homozygous animals, C57 BL/KsJ-db/db micedeveloped by Jackson Laboratory, US, are obese, hyperglycemic,hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85:962-967), whereas heterozygous are lean and normoglycemic. In db/dbmodel, mouse progressively develops insulinopenia with age, a featurecommonly observed in late stages of human type II diabetes when bloodsugar levels are insufficiently controlled. The state of pancreas andits course vary according to the models. Since this model resembles thatof type II diabetes mellitus, the compounds of the present inventionwill be tested for blood sugar and triglycerides lowering activities.

Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight rangeof 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animalhouse, were used in the experiment. The mice are provided with standardfeed (National Institute of Nutrition (NIN), Hyderabad, India) andacidified water, ad libitum. The animals having more than 350 mg/dlblood sugar will be used for testing. The number of animals in eachgroup was 4.

Test compounds are suspended on 0.25% carboxymethyl cellulose andadministered to test group at a dose of 0.1 mg to 30 mg/kg through oralgavage daily for 6 days. The control group receives vehicle (dose 10ml/kg). On 6th day the blood samples will be collected one hour afteradministration of test compounds/vehicle for assessing the biologicalactivity.

The random blood sugar and triglyceride levels can be measured bycollecting blood (100 μl) through orbital sinus, using heparinisedcapillary in tubes containing EDTA which was centrifuged to obtainplasma. The plasma glucose and triglyceride levels can be measuredspectrometrically, by glucose oxidase and glycerol-3-PO₄oxidase/peroxidse enzyme (Dr. Reddy's Lab. Diagnostic Division Kits,Hyderabad, India) methods respectively.

The blood sugar and triglycerides lowering activities of the testcompound are calculated according to the formula.

No adverse effects were observed for any of the mentioned compounds ofinvention in the above test. Reduction in Blood Triglyceride CompoundDose (mg/kg) Glucose Level (%) Lowering (%)  3 3 33 29 18 3 16 35

The ob/ob mice were obtained at 5 weeks of age from Bornholtgard,Denmark and were used at 8 weeks of age. Zucker fa/fa fatty rats wereobtained from IffaCredo, France at 10 weeks of age and were used at 13weeks of age. The animals were maintained under 12 hour light and darkcycle at 25 ±1° C. Animals were given standard laboratory chow (NIN,Hyderabad, India) and water, ad libiturn (Fujiwara, T., Yoshioka, S.,Yoshioka, I., Ushiyama, I and Horikoshi, H. Characterization of new oralanitidiabetic agent CS-045. Studies in KK and ob/ob mice and Zuckerfatty rats. Diabetes. 1988. 37: 1549-1558).

The test compounds were administered at 0.1 to 30 mg/kg dose for 9 days.The control animals received the vehicle (0.25% carboxymethylcelllose,dose 10 mL/kg) through oral gavage.

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 9 day of treatment The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride, glucose, free fatty acid, total cholesterol and insulinestimations. Measurement of plasma triglyceride, glucose, totalcholesterol was done using commercial kits (Dr. Reddy's Laboratory,Diagnostic Division, India). The plasma free fatty acid was measuredusing a commercials kit from Boehringer Mannheim, Germany. The plasmainsulin was measured using a RIA kit (BARC, India). The reduction ofvarious parameters examined are calculated according to the formulagiven below.

In ob/ob mice oral glucose tolerance test was performed after 9 daystreatment. Mice were fasted for 5 hrs and challenged with 3 gm/kg ofglucose orally. The blood samples were collected at 0, 15, 30, 60 and120 min for estimation of plasma glucose levels.

The experimental results from the db/db mice, ob/ob mice, Zucker falfarats suggest that the novel compounds of the present invention alsopossess therapeutic utility as a prophylactic or regular treatment fordiabetes, obesity, cardiovascular disorders such as hypertension,hyperlipidaemia and other diseases; as it is known from the literaturethat such diseases are interrelated to each other.

Blood glucose level and triglycerides are also lowered at doses greaterthan 10 mg/kg. Normally, the quantum of reduction is dose dependent andplateaus at certain dose.

b) Plasma Triglyceride and Cholesterol Lowering Activity inHypercholesterolemic Rat Models

Male Sprague Dawley rats (NIN stock) were bred in DRF animal house.Animals were maintained under 12 hour light and dark cycle at 25 ±1° C.Rats of 180-200 gram body weight range were used for the experiment.Animals are made hypercholesterolemic by feeding 2% cholesterol and 1%sodium cholate mixed with standard laboratory chow [National Instituteof Nutrition (NIN), Hyderabad, India] 30 for 6 days. Throughout theexperimental period the animals were maintained on the same diet (Petit,D., Bonnefis, M. T., Rey, C and Inafante, R. Effects of ciprofibrate onliver lipids and lipoprotein synthesis in normo- and hyperlipidemicrats. Atherosclerosis. 1988. 74: 215-225).

The test compounds can be administered orally at a dose 0.1 to 30mg/kg/day for 3 days. Control group was treated with vehicle alone(0.25% Carboxymethylcellulose; dose 10 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 3 day of compound treatment. The blood wascollected from the retro-orbital sinus through heparinsed capillary inEDTA containing tubes. After centrifugation, plasma sample was separatedfor total cholesterol, HDL and triglyceride estimations. Measurement ofplasma, triglyceride, total cholesterol and HDL are were done usingcommercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India).LDL and VLDL cholesterol were calculated from the data obtained fortotal cholesterol, HDL and triglyceride. The reduction of variousparameters examined are calculated according to the formula. TotalExample Dose Triglyceride Cholesterol HDL LDL VLDL No. mg/kg (%) ↓ (%) ↓(%) ↑ (%) ↓ (%) ↓  3 10 77 69 254 80 77 18 10 77 64 260 74 77↓ reduction;↑ increasec) Plasma Triglyceride and Total Cholesterol Lowering Activity in SwissAlbino Mice and Gunie Pigs

Male Swiss albino mice (SAM) and male Guinea pigs were obtained from NINand housed in DRF animal house. All these animals are maintained under12 hour light and dark cycle at 25 ±1° C. Animals were given standardlaboratory chow (NIN, Hyderabad, India) and water, ad libitum. SAM of20-25 g body weight range and Guinea pigs of 500-760 g body weight rangeare used (Oliver, P., Plancke, M. O., Marzin, D., Clavey, V., Sauzieres,J and Fruchatt, J. C. Effects of fenofibrate, gemfibrozil and nicotinicacid on plasma lipoprotein levels in normal and hyperlipidemic mice.Atherosclerosis. 1988. 70: 107-114).

The test compounds were administered orally to Swiss albino mice at 0.3to 30 mg/kg/day dose for 6 days. Control mice are treated with vehicle(0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds areadministered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6days. Control animals are treated with vehicle (0.25%Carboxymethylcellulose; dose 5 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 6 day of treatment The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride and total cholesterol (Wieland, O. Methods of Enzymaticanalysis. Bergermeyer, H. O., Ed., 1963. 211-214; Trinder, P. Ann. Clin.Biochem. 1969. 6: 24-27). Measurement of plasma triglyceride were doneusing commercial kits (Dr. Reddy's Diagnostic Division, Hyderabad,India). Compound Dose (mg/kg) Triglyceride Lowering (%)  3 10 70  6 1027 15 10 43 18 10 61d) Body Weight Reducing Effect in Cholesterol Fed Hamsters:

Male Syrian Hamsters were procured from NIN, Hyderabad, India. Animalswere housed at DRF animal house under 12 hour light and dark cycle at 25±1° C. with free access to food and water. Animals are maintained with1% cholesterol containing standard laboratory chow (NIN) from the day oftreatment.

The test compounds can be administered orally at 1 to 30 mg/kg/day dosefor 15 days. Control group animals were treated with vehicle (Mill Qwater, dose 10 ml/kg/day). Body weights are measured on every 3^(rd)day.

Formulae for Calculation:

1. Percent reduction in Blood sugar/triglycerides/total cholesterol willbe calculated according to the formula:${{Percent}\quad{reduction}\quad(\%)} = {\left\lbrack {1 - \frac{{TT}/{OT}}{{TC}/{OC}}} \right\rbrack \times 100}$

-   -   OC=Zero day control group value    -   OT=Zero day treated group value    -   TC=Test day control group value    -   TT=Test day treated group value

2. LDL and VLDL cholesterol levels will be calculated according to theformula: $\begin{matrix}{\begin{matrix}{{LDL}\quad{cholesterol}} \\{{in}\quad{mg}\text{/}\text{dl}}\end{matrix} = \left\lbrack {{{Total}\quad{cholesterol}} - {{HDL}\quad{cholesterol}} -} \right.} \\{\left. \frac{Triglyceride}{5} \right\rbrack\quad{mg}\text{/}\text{dl}}\end{matrix}$  VLDL cholesterol in mg/dl=[Total cholesterol−HDLcholesterol−LDL cholesterol]mg/dl.

1. A compound of formula (I)

its derivatives, its analogs, it tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, or itspharmaceutically acceptable solvates wherein R¹, R² and R³, R⁴ whenattached to the carbon atom, are the same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or a substituted orunsubstituted group selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R³ and R⁴ represents oxo or thioxo group attached tocarbon atom; R³ and R⁴ when attached to a nitrogen atom representhydrogen, hydroxy, formyl or a substituted or unsubstituted groupselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino,aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylicacid derivatives, or sulfonic acid derivatives; X represents aheteroatom selected from oxygen or sulfur; W represents NR¹²,—C(═O)—(CR¹⁰OR¹¹)_(o)NR¹², or —O-aryl-(CR¹⁰OR¹¹). NR¹², where R¹²represents hydrogen or a substituted or unsubstituted group selectedfrom alkyl, aryl or aralkyl group; o is an integer of from 0 to 6; R¹⁰and R¹¹ are same or different and represent hydrogen or an unsubstitutedor unsubstituted group selected from alkyl, alkoxy, aryl or aralkylgroup; Ar represents a substituted or unsubstituted divalent single orfused aromatic or heterocyclic group selected from divalent phenylene,naphthylene, pyrrolyl, pyridyl, quinolinyl, benzofuryl,dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl,indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl orbenzoxazolyl; R⁵ represents hydrogen atom, hydroxy, alkoxy, halogen,alkyl, substituted or unsubstituted aralkyl group or forms a bondtogether with the adjacent group R⁶; R⁶ represents hydrogen, hydroxy,alkoxy, halogen, alkyl group, acyl, substituted or unsubstituted aralkylor R⁶ forms a bond together with R⁵; R⁷ represents hydrogen or asubstituted or unsubstituted group selected from alkyl, cycloalkyl,aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl R⁸ represents hydrogen or a substituted orunsubstituted group selected from alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl or heteroaralkyl; Y represents oxygen, sulfuror NR⁹, where R⁹ represents hydrogen or a substituted or unsubstitutedgroup selected from alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl,heteroaryl, or heteroaralkyl or NR⁹ represents chiral amine, or a chiralamine alcohol derived from a chiral amino acid; or R⁸ and R⁹ togetherform a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, which optionally contains one or moreheteroatoms selected from oxygen, sulfur or nitrogen; and m and n areintegers from 0 to
 6. 2. A compound according to claim 1, wherein whenR¹, R², R³ or R⁴ are substituted the substituents are selected fromhalogen, hydroxyl, nitro, thio or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,aryloxy, aralkoxy, alkoxyalkyl, aryloxyalkyl, arolkoxyalkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino,alkylthio groups, carboxylic acid or its derivatives or sulfonic acid orits derivatives.
 3. A compound according to claim 1, wherein R¹, R², R³,or R⁴ when attached to the carbon atom, are the same or different andrepresent hydrogen, halogen or alkyl; or one or both of R³ and R⁴represent oxo or thioxo group when attached to a carbon atom; or one orboth of R³ and R⁴ when attached to nitrogen atom represent hydrogen oralkyl; R⁵ represents a hydrogen atom or forms a bond together with theadjacent group R⁶; R⁶ represents hydrogen or forms a bond together withR⁵; R⁷ represents hydrogen or substituted or unsubstituted alkyl, arylor aralkyl; R⁵ represents hydrogen or substituted or unsubstitutedgroups selected from alkyl, aryl or aralkyl; and m and n are integersfrom 0 to
 2. 4. A compound according to claim 1, which is selected fromthe group consisting of: (±) Ethyl3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(+) Ethyl3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(−) Ethyl3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(±)3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (+)3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (−)3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2ethoxypropanoicacid or its salts; (±)Ethyl-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate;(+) Ethyl 3-[4N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate;(−) Ethyl3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate;(±)3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-ethylamino}phenyl]-2-ethoxypropanoicacid or its salts; (+)3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoicacid or its salts; (−)3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoicacid or its salts; (±) Methyl2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate;(+) Methyl2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-y 1)-2-oxoethyl)aminomethyl}phenyl]propanoate; (−) Methyl2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate;(±)2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoicacid or its salts; (+)2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoicacid or its salts; (−)2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoicacid or its salts; (±) Methyl3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate;(+) Methyl3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate;(−) Methyl3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate;(±)3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoicacid ox its salts; (+)3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoicacid or its salts; (−)3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoicacid or its salts; (±) Methyl3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (+) Methyl3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (−) Methyl3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]2-ethoxypropanoate; (±)3-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2ethoxypropanoicacid or its salts; (+)3-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2,ethoxypropanoicacid or its salts; (−)3-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2ethoxypropanoicacid or its salts; (±) Methyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(+) Methyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(−) Methyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(±)3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (+)3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid ox its salts; (−)3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts, (±) Methyl2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4yl)propyloxy)benzyl}aminophenyl]propanoate;(+) Methyl2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4yl)propyloxy)benzyl}aminophenyl]propanoate;(−) Methyl2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4yl)propyloxy)benzyl}aminophenyl]propanoate;(±) Methyl2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;(+) Methyl2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;(−) Methyl2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;(±)2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid or its salts; (+)2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid or its salts; (−)2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid or its salts; (±)2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid or its salts; (+)2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid or its salts; (−)2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoicacid or its salts; (±) Ethyl2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate;(+) Ethyl2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate;(−) Ethyl2-ethoxy-3-[4;{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4yl)propylamino}phenyl]propanoate;(±)2-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoicacid or its salts; (+)2-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4yl)propylamino}phenyl]propanoicacid or its salts; (−)2-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4yl)propylamino}phenyl]propanoicacid or its salts; (±) Ethyl2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate;(+) Ethyl2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate;(−) Ethyl2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate;(±)2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoicacid or its salts; (+)2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoicacid or its salts; (−)2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoicacid or its salts; (±) Methyl2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate;(+) Methyl2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate;(−) Methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2Hbenzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate; (±)2-Ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoicacid or its salts; (+)2-Ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoicacid or its salts; (−)2-Ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoicacid or its salts; (±) Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(+) Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(−) Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;{±) Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(+) Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2I-r-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(−) Ethyl3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(±)3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid or its salts; (+)3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid or its salts; (−)3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid ox its salts; (±) Ethyl3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(+) Ethyl3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(−) Ethyl3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(±)3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (+)3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (−)3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (±) Ethyl3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(+) Ethyl3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(−) Ethyl3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(±)3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (+)3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (−)3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (±) Ethyl3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(+) Ethyl3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(−) Ethyl3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(±)3-(4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid or its salts; (+)3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid or its salts; (−)3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid or its salts; (±) Ethyl3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(+) Ethyl3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(−) Ethyl3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;(±)3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (+)3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (−)3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoicacid or its salts; (±) Ethyl(2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(+) Ethyl (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2Hbenzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (−)Ethyl(2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(±)3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid and its salts; (+)3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid and its salts; (−)3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid and its salts; (±) Ethyl2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino)phenyl]propanoate;(+) Ethyl2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino)phenyl]propanoate;(−) Ethyl2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate;(±)2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoicacid and its salts; (+)2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoicacid and its salts; (−)2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino)phenyl]propanoicacid and its salts; (±) Ethyl3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(+) Ethyl3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(−) Ethyl3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate;(±)3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid and its salts; (+)3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid anal its salts; (−)3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoicacid and its salts;[2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;[2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;[2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;[2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamidehydrochloride salt; and[2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamidehydrochloride salt;
 5. A compound according to claim 1, wherein thepharmaceutically acceptable salt is selected from the group consistingof Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; NN′-diacetylethylenediamine,betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine,piperidine, procaine, purines, theobromine, triethylamine,trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine,ethylenediamine, N,N′-diphenylethylenediamine,N,N′dibenzylethylenediamine, N-benzyl phenylethylamine, choline, cholinehydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine,dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine,purine, spermidine; alkylphenylamine, glycinol, phenyl glycinol;glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine,cystine, cysteine, methionine, proline, hydroxy proline, histidine,ornithine, lysine, arginine, serine, threonine, phenylalanine; unnaturalamino acids; D-isomers or substituted amino acids; guanidine,substituted guanidine wherein the substituents are selected from nitro,amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium saltsand aluminum salts; sulphates, nitrates, phosphates, perchlorates,borates, hydrohalides, acetates, tartrates, maleates, citrates,succinates, palmoates, methanesulphonates, benzoates, salicylates,hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates,ketoglutarates, ammonium or substituted ammonium salts or aluminiumsalt.
 6. A process for the preparation of the compound of formula (I)

as defined in claim 1 which comprises: a. reacting a compound of formula(IIIa)

where L¹ is a leaving group and all other symbols are as defined inclaim 1 with a compound of formula (IIIb)

where W represents NR¹² or —O-aryl (CR¹⁰R¹¹)_(o)—NR¹² and all symbolsare as defined above to yield a compound of formula (I) defined above;or b. reacting a compound of formula (IIIc)

where all symbols are as defined in claim 1 with a compound of formula(IIId)

where L¹ is a leaving group, W represents NR¹² or—O-aryl-(CR¹⁰R¹¹)_(o)—NR¹² and all other symbols are as defined in claim1 to produce a compound of formula (I); or c. reacting a compound offormula (IIIe)

where W represents NR¹² or —O-aryl-(CR¹⁰R¹¹)_(o)—NR¹² and all symbolsare as defined in claim 1 with a compound of formula (IIIf)

where R¹³ represents (C₁-C₆)alkyl and all other symbols are as definedabove in claim 1 to a yield compound of formula (I) as defined above,and optionally, converting the compound of formula (I) obtained in anyof the processes described above into a pharmaceutically acceptable saltor a pharmaceutically acceptable solvate; or d. reacting a compound offormula (IVa)

which represents a compound of formula (I) where R⁵ and R⁶ togetherrepresent a bond and Y represents an oxygen atom and all other symbolsare as defined in claim 1, prepared according to any of the processesdefined in claim 5, to yield a compound of the formula (I) where R⁵ andR⁶ each represent hydrogen atom and all other symbols are as definedabove; or e. reacting a compound of formula (IIIe)

where W represents NR¹² or —O-aryl-(CR¹⁰R¹¹)_(o)NR¹² and all othersymbols are as defined above with a compound of formula (IVb)

where R⁵ represents hydrogen and all other symbols are as defined aboveto yield compound of formula (I) defined above, or f. reacting acompound of formula (IIIg)

where L¹ is a leaving group, n and o are integers from 0 to 6 and allother symbols are as defined above, with a compound of formula (IIIb)

where W represents NR¹² and all other symbols are as defined above toyield a compound of formula (I) where W represents—C(═O)—(CR¹⁰R¹¹)_(o)—NR¹² and all other symbols are as defined above; org. reacting a compound of formula (IIIi)

where n and p are integers from 0 to 6, G¹ is CHO or NH₂ and all othersymbols are as defined above with a compound of formula (IIIh)

where q is an integer ranging from 0 to 6, G₂ is CHO or NH₂ and allother symbols are as defined above to yield a compound of formula (I)where W represents —O-aryl(CR¹⁰R¹¹)_(o)—NR¹² and all other symbols areas defined above; or h. i. reacting a compound of formula (I)

where all symbols are as defined above and Y represents oxygen or YR⁸represents a halogen atom or COYR⁸ represent a mixed anhydride group andall other symbols are as defined above with an amine of formula NHR⁸R⁹where R⁸ and R⁹ are as defined above and optionally; ii. resolving thecompound of formula (I) obtained above into stereoisomers, or i.hydrolyzing a compound of formula (I)

where R⁸ represents an unsubstituted or substituted group selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl group and all other symbols are as defined above to acompound of formula (I) where R⁸ represents hydrogen, optionallyconverting the compound of formula (I) obtained in any of the processesdefined above into a pharmaceutically acceptable salt orpharmaceutically acceptable solvate.
 7. An intermediate of formula(IIId)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, their pharmaceutically acceptable salts, or itspharmaceutically acceptable solvates wherein L¹ is a leaving groupselected from the group consisting of as halogen atom, methanesulfonate,trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonateacetate, sulfate, phosphate and hydroxy; W represents NR¹²,—C(═O)—(CR¹⁰R¹¹)_(o)—NR¹², or —O-aryl-(CR¹⁰R¹¹)_(o)—NR¹², where R¹²represents hydrogen or a substituted or unsubstituted group selectedfrom alkyl, aryl or aralkyl; o is an integer from 0 to 4; R¹⁰ and R¹¹are the same or different and represent hydrogen or an unsubstituted orunsubstituted group selected from alkyl, alkoxy, aryl or aralkyl group;Ar represents a substituted or unsubstituted divalent single or fusedaromatic or heterocyclic group; R⁵ represents hydrogen atom, hydroxy,alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group orforms a bond together with the adjacent group R⁶; R⁶ representshydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, substitutedor unsubstituted aralkyl or R⁶ forms a bond together with R⁵; R⁷represents hydrogen or a substituted or unsubstituted group selectedfrom alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,heterocyclyl, heteroaryl, or heteroaralkyl; R⁸ represents hydrogen or asubstituted or unsubstituted group selected from alkyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl; Y representsoxygen, sulfur or NR⁹, where R⁹ represents hydrogen or a substituted orunsubstituted group selected from alkyl, aryl, hydroxyalkyl, aralkylheterocyclyl, heteroaryl, or heteroaralkyl; or R⁸ and R⁹ together form asubstituted or unsubstituted 5 or 6 membered cyclic structure containingcarbon atoms, which optionally contains one or more heteroatoms selectedfrom oxygen, sulfur or nitrogen; and m and n are integers from 0 to 6.8. An intermediate of formula (IIIg)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, their pharmaceutically acceptable salts, or itspharmaceutically acceptable solvates wherein R¹, R², and R³, or R⁴ whenattached to a carbon atom, are the same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted orunsubstituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or, its derivatives, or sulfonic acid or itsderivatives; or one or both of R³ and R⁴ represent oxo or thioxo groupwhen they are attached to carbon atom; or R³, R⁴ or both when attachedto nitrogen atom represent hydrogen, hydroxy, formyl or optionallysubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy,heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid derivatives, or sulfonic acid derivatives; X representsa heteroatom selected from oxygen or sulfur; R¹⁰ and R¹¹ are the same ordifferent and represent hydrogen or substituted or unsubstituted groupselected from alkyl, alkoxy, aryl or aralkyl group; L¹ is a leavinggroup selected from the group consisting of halogen atom,methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate,p-nitrobenzenesulfonate, acetate, sulfate, phosphate or and hydroxy; andn and o are integers from 0 to
 6. 9. An intermediate of formula (IIIi)

its derivatives, it analogs, its tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, or itspharmaceutically acceptable solvates wherein R¹, R², and R³, or R⁴ whenattached to the carbon atom, are the same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted orunsubstituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;or one or both of R³ and R⁴ represent oxo or thioxo group when they areattached to carbon atom; or R³, and R⁴ or both when attached to nitrogenatom represent hydrogen, hydroxy, formyl or optionally substitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy,heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid derivatives, or sulfonic acid derivatives; X representsa heteroatom selected from oxygen or sulfur; R¹⁰ and R¹¹ are same ordifferent and represent hydrogen or substituted or unsubstituted groupselected form alkyl, alkoxy, aryl or aralkyl group; G¹ is CHO or NH₂, an and p are integers from 0 to
 6. 10. A pharmaceutical composition,which comprises a compound of formula (I) as defined in claim 1 and apharmaceutically acceptable carrier, diluent, excipient or solvate. 11.A pharmaceutical composition which comprises a compound of formula (I)as defined in claim 1 and a HMG CoA reductase inhibitor; fibrate;nicotinic acid; cholestyramine; cholestipol; probucol or a combinationthereof and a pharmaceutically acceptable carrier, diluent, excipient orsolvate.
 12. The pharmaceutical composition as claimed in claim 10 inthe form of a tablet, capsule, powder, syrup, solution or suspension.13. A method of preventing or treating hyperlipemia, hypercholesteremia,hyperglycemia, osteoporosis, obesity, impaired glucose tolerance,atherosclerosis, leptin resistance, insulin resistance or a disease inwhich insulin resistance is the underlying pathophysiological mechanismcomprising administering a compound of formula (I) as defined in claim 1to a patient in need thereof.
 14. The method according to claim 13,wherein the disease is type II diabetes, impaired glucose tolerance,dyslipidemia, disorders related to Syndrome X including hypertension,obesity, insulin resistance, coronary artery disease and othercardiovascular disorders; renal diseases including glomerulonephritis,glomeruloscierosis, nephrotic syndrome, hypertensive nephrosclerosis,retinopathy, nephropathy, disorders to related endothelial cellactivation, psoriasis, polycystic ovarian syndrome (PCOS), dementia,diabetic complications, inflammatory bowel diseases, myotonic dystrophy,pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or,osteoporosis or as an inflammatory agent.
 15. A method for the treatmentand/or prophylaxis of disorders related to Syndrome X, which comprisesadministering an agonist of PPARα and/or PPARγ of formula (I) as definedin claim 1 to a patient in need thereof.
 16. A method of reducing totalcholesterol, body weight, blood plasma glucose, triglycerides, LDL, VLDLor free fatty acids or increasing HDL in the plasma comprisingadministering a compound of formula (I), as defined in a claim 1 to apatient in need thereof.
 17. A compound according to claim 1, whereinwhen R⁷ is substituted, the substituent is selected from alkyl,cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy,alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio,thioalkyl groups, carboxylic acid or its derivatives or sulfonic acid orits derivatives.
 18. A pharmaceutical composition, which comprises acompound of formula (I) as defined in claim 2 and a pharmaceuticallyacceptable carrier, diluent, excipient or solvate.
 19. A pharmaceuticalcomposition, which comprises a compound of formula (I) as defined inclaim 3 and a pharmaceutically acceptable carrier, diluent, excipient orsolvate.
 20. A pharmaceutical composition, which comprises a compound asdefined in claim 4 and a pharmaceutically acceptable carrier, diluent,excipient or solvate.
 21. A pharmaceutical composition, which comprisesa compound of formula (I) as defined in claim 5 and a pharmaceuticallyacceptable carrier, diluent, excipient or solvate.
 22. A pharmaceuticalcomposition which comprises a compound as defined in claim 4 and a HMGCoA reductase inhibitor; fibrate; nicotinic acid; cholestyramine;cholestipol; probucol or a combination thereof and a pharmaceuticallyacceptable carrier, diluent, excipient or solvate.
 23. A pharmaceuticalcomposition which comprises a compound as defined in claim 5 and a HMGCoA reductase inhibitor; fibrate; nicotinic acid; cholestyramine;cholestipol; probucol or a combination thereof and a pharmaceuticallyacceptable carrier, diluent, excipient or solvate.
 24. Thepharmaceutical composition as claimed in claim 11 in the form of atablet, capsule, powder, syrup, solution or suspension.
 25. Thepharmaceutical composition as claimed in claim 18 in the form of atablet, capsule, powder, syrup, solution or suspension.
 26. Thepharmaceutical composition as claimed in claim 19 in the form of atablet, capsule, powder, syrup, solution or suspension
 27. Thepharmaceutical composition as claimed in claim 20 in the form of atablet, capsule, powder, syrup, solution or suspension.
 28. Thepharmaceutical composition as claimed in claims 21 in the form of atablet, capsule, powder, syrup, solution or suspension
 29. Thepharmaceutical composition as claimed in claim 22 in the form of atablet, capsule, powder, syrup, solution or suspension.
 30. Thepharmaceutical composition as claimed in claim 23 in the form of atablet, capsule, powder, syrup, solution or suspension.
 31. A method ofpreventing or treating hyperlipemia, hypercholesteremia, hyperglycemia,osteoporosis, obesity, impaired glucose tolerance, atherosclerosis,leptin resistance, insulin resistance or diseases in which insulinresistance is the underlying pathophysiological mechanism comprisingadministering a compound of formula (I) as defined in claim 4 to apatient in need thereof.
 32. A method of preventing or treatinghyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity,impaired glucose tolerance, atherosclerosis, leptin resistance, insulinresistance or diseases in which insulin resistance is the underlyingpathophysiological mechanism comprising administering a compound offormula (I) as defined in claim 5 to a patient in need thereof.
 33. Amethod of preventing or treating hyperlipemia, hypercholesteremia,hyperglycemia, osteoporosis, obesity, impaired glucose tolerance,atherosclerosis, leptin resistance, insulin resistance or diseases inwhich insulin resistance is the underlying pathophysiological mechanismcomprising administering a pharmaceutical composition as claimed inclaim 10 to a patient in need thereof.
 34. A method of preventing ortreating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis,obesity, impaired glucose tolerance, atherosclerosis, leptin resistance,insulin resistance or diseases in which insulin resistance is theunderlying pathophysiological mechanism comprising administering apharmaceutical composition as claimed in claim 11 to a patient in needthereof.
 35. A method of preventing or treating hyperlipemia,hypercholesteremia, hyperglycemia, osteoporosis, obesity, impairedglucose tolerance, atherosclerosis, leptin resistance, insulinresistance or diseases in which insulin resistance is the underlyingpathophysiological mechanism comprising administering a pharmaceuticalcomposition as claimed in claim 20 to a patient in need thereof.
 36. Amethod of preventing or treating hyperlipemia, hypercholesteremia,hyperglycemia, osteoporosis, obesity, impaired glucose tolerance,atherosclerosis, leptin resistance, insulin resistance or diseases inwhich insulin resistance is the underlying pathophysiological mechanismcomprising administering a pharmaceutical compound as claimed in claim21 to a patient in need thereof.
 37. A method of preventing or treatinghyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity,impaired glucose tolerance, atherosclerosis, leptin resistance, insulinresistance or diseases in which insulin resistance is the underlyingpathophysiological mechanism comprising administering a compound offormula (I) as defined in claim 22 to a patient in need thereof.
 38. Amethod of preventing or treating hyperlipemia, hypercholesteremia,hyperglycemia, osteoporosis, obesity, impaired glucose tolerance,atherosclerosis, leptin resistance, insulin resistance or diseases inwhich insulin resistance is the underlying pathophysiological mechanismcomprising administering a pharmaceutical compound as claimed in claim23 to a patient in need thereof.
 39. A method of preventing or treatinghyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity,impaired glucose tolerance, atherosclerosis, leptin resistance, insulinresistance or diseases in which insulin resistance is the underlyingpathophysiological mechanism comprising administering a pharmaceuticalcompound as claimed in claim 29 to a patient in need thereof.
 40. Amethod of preventing or treating hyperlipemia, hypercholesteremia,hyperglycemia, osteoporosis, obesity, impaired glucose tolerance,atherosclerosis, leptin resistance, insulin resistance or diseases inwhich insulin resistance is the underlying pathophysiological mechanismcomprising administering a pharmaceutical compound as claimed in claim30 to a patient in need thereof.
 41. A method according to claim 31,wherein the disease is type II diabetes, impaired glucose tolerance,dyslipidemia, disorders related to Syndrome X including hypertension,obesity, insulin resistance, coronary artery disease and othercardiovascular disorders; renal diseases including glomerulonephritis,glomeruloscierosis, nephrotic syndrome, hypertensive nephrosclerosis,retinopathy, nephropathy, disorders to related endothelial cellactivation, psoriasis, polycystic ovarian syndrome (PCOS), dementia,diabetic complications, inflammatory bowel diseases, myotonic dystrophy,pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or,osteoporosis or as inflammatory agents.
 42. A method according to claim32, wherein the disease is type II diabetes, impaired glucose tolerance,dyslipidemia, disorders related to Syndrome X including hypertension,obesity, insulin resistance, coronary artery disease and othercardiovascular disorders; renal diseases including glomerulonephritis,glomeruloscierosis, nephrotic syndrome, hypertensive nephrosclerosis,retinopathy, nephropathy, disorders to related endothelial cellactivation, psoriasis, polycystic ovarian syndrome (PCOS), dementia,diabetic complications, inflammatory bowel diseases, myotonic dystrophy,pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or,osteoporosis or as an inflammatory agents.
 43. A method according toclaim 33, wherein the disease is type II diabetes, impaired glucosetolerance, dyslipidemia, disorders related to Syndrome X includinghypertension, obesity, insulin resistance, coronary artery disease andother cardiovascular disorders, renal diseases includingglomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensivenephrosclerosis, retinopathy, nephropathy, disorders to relatedendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), dementia, diabetic complications, inflammatory bowel diseases,myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eatingdisorders, cancer or, osteoporosis or as an inflammatory agent.
 44. Amethod according to claim 34, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX including hypertension, obesity, insulin resistance, coronary arterydisease and other cardiovascular disorders; renal diseases includingglomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensivenephrosclerosis, retinopathy, nephropathy, disorders to relatedendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), dementia, diabetic complications, inflammatory bowel diseases,myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eatingdisorders, cancer or, osteoporosis or as an inflammatory agent.
 45. Amethod according to claim 35, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX including hypertension, obesity, insulin resistance, coronary arterydisease and other cardiovascular disorders, renal diseases includingglomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensivenephrosclerosis, retinopathy, nephropathy, disorders to relatedendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), dementia, diabetic complications, inflammatory bowel diseases,myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eatingdisorders, cancer or, osteoporosis or as an inflammatory agent.
 46. Amethod according to claim 36, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX including hypertension, obesity, insulin resistance, coronary arterydisease and other cardiovascular disorders; renal diseases includingglomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensivenephrosclerosis, retinopathy, nephropathy, disorders to relatedendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), dementia, diabetic complications, inflammatory bowel diseases,myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eatingdisorders, cancer or, osteoporosis or as an inflammatory agent.
 47. Amethod according to claim 37, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX including hypertension, obesity, insulin resistance, coronary arterydisease and other cardiovascular disorders; renal diseases includingglomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensivenephrosclerosis, retinopathy, nephropathy, disorders to relatedendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), dementia, diabetic complications, inflammatory bowel diseases,myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eatingdisorders, cancer or, osteoporosis or as an inflammatory agent.
 48. Amethod according to claim 38, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX including hypertension, obesity, insulin resistance, coronary arterydisease and other cardiovascular disorders; renal diseases includingglomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensivenephrosclerosis, retinopathy, nephropathy, disorders to relatedendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), dementia, diabetic complications, inflammatory bowel diseases,myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eatingdisorders, cancer or, osteoporosis or as an inflammatory agent.
 49. Amethod according to claim 39, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX including hypertension, obesity, insulin resistance, coronary arterydisease and other cardiovascular disorders; renal diseases includingglomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensivenephrosclerosis, retinopathy, nephropathy, disorders to relatedendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), dementia, diabetic complications, inflammatory bowel diseases,myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eatingdisorders, cancer or, osteoporosis or as an inflammatory agent.
 50. Amethod according to claim 40, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX including hypertension, obesity, insulin resistance, coronary arterydisease and other cardiovascular disorders; renal diseases includingglomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensivenephrosclerosis, retinopathy, nephropathy, disorders to relatedendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), dementia, diabetic complications, inflammatory bowel diseases,myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eatingdisorders, cancer or, osteoporosis or as an inflammatory agent.
 51. Amethod for the treatment and/or prophylaxis of disorders related toSyndrome X, which comprises administering an agonist of PPARα and/orPPARγ of formula (I) as defined in claim 4 to a patient in need thereof.52. A method for the treatment and/or prophylaxis of disorders relatedto Syndrome X, which comprises administering an agonist of PPARα and/orPPARγ of formula (I) as defined in claim 5 to a patient in need thereof.53. A method for the treatment and/or prophylaxis of disorders relatedto Syndrome X, which comprises administering a composition as defined inclaim 10 to a patient in need thereof.
 54. A method for the treatmentand/or prophylaxis of disorders related to Syndrome X, which comprisesadministering a composition as defined in 11 to a patient in needthereof.
 55. A method for the treatment and/or prophylaxis of disordersrelated to Syndrome X, which comprises a composition administering anagonist of PPARα and/or PPARγ as defined in claim 19 to a patient inneed thereof.
 56. A method for the treatment and/or prophylaxis ofdisorders related to Syndrome X, which comprises a compositionadministering an agonist of PPARα and/or PPARγ as defined in claim 20 toa patient in need thereof.
 57. A method according to claim 13, for thetreatment and/or prophylaxis of disorders related to Syndrome X, whichcomprises administering a composition as defined in claim 21 to apatient in need thereof.
 58. A method of reducing total cholesterol,body weight, blood plasma glucose, triglycerides, LDL, VLDL or freefatty acids or increasing HDL in the plasma comprising administering apharmaceutical composition according to claim 4 to a patient in needthereof.
 59. A method of reducing total cholesterol, body weight, bloodplasma glucose, triglycerides, LDL, VLDL or free fatty acids orincreasing HDL in the plasma comprising administering a pharmaceuticalcomposition according to claim 5 to a patient in need thereof.
 60. Amethod of reducing total cholesterol, body weight, blood plasma glucose,triglycerides, LDL, VLDL or free fatty acids or increasing HDL in theplasma comprising administering a compound of formula (I), as defined inclaim 10 to a patient in need thereof.
 61. A method of reducing totalcholesterol, body weight, blood plasma glucose, triglycerides, LDL, VLDLor free fatty acids or increasing HDL in the plasma comprisingadministering a compound of formula (I), as defined in claim 11 to apatient in need thereof.
 62. A method of reducing total cholesterol,body weight, blood plasma glucose, triglycerides, LDL, VLDL or freefatty acids or increasing HDL in the plasma comprising administering apharmaceutical composition according to claim 20 to a patient in needthereof.
 63. A method of reducing total cholesterol, body weight, bloodplasma glucose, triglycerides, LDL, VLDL or free fatty acids orincreasing HDL in the plasma comprising administering a pharmaceuticalcomposition according to claim 22 to a patient in need thereof.
 64. Amethod for the treatment and/or prophylaxis of disorders related toSyndrome X, which comprises administering an agonist of PPARα and/orPPARγ as defined in claim 23 to a patient in need thereof.
 65. A methodof reducing total cholesterol, body weight, blood plasma glucose,triglycerides, LDL, VLDL or free fatty acids or increasing HDL in theplasma comprising administering a pharmaceutical composition accordingto claim 23 to a patient in need thereof.